Benzothiophene estrogen receptor modulators

ABSTRACT

This invention is a benzothiophene estrogen receptor modulator or its pharmaceutically acceptable salt or a pharmaceutically acceptable composition thereof to treat an estrogen-related medical disorder.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application62/457,643 filed on Feb. 10, 2017; U.S. Provisional Application62/460,358 filed on Feb. 17, 2017; and U.S. Provisional Application62/614,279 filed on Jan. 5, 2018; the entirety of each of which ishereby incorporated by reference for all purposes.

FIELD OF THE INVENTION

This invention is directed to benzothiophene compounds with basicsubstituents and their compositions to treat estrogen related disorders.

BACKGROUND

Estrogens modulate a range of metabolic processes in humans, notably,reproduction, cardiovascular health, bone integrity, cognition andbehavior. Estrogen also plays a central role in a wide range of humandiseases, including various types of cancer (for example, breast,ovarian, colorectal, prostate, kidney and endometrial), osteoporosis,neurodegenerative diseases, cardiovascular disease, insulin resistance,lupus erythematosus, endometriosis, and obesity. In many of thesedisorders, estrogen mediates the disease through the estrogen receptor.Deroo, et al., Estrogen Receptors and Human Disease, J. Clin. Invest.2006 Mar. 1, 116(3):561-570.

Estrogen receptors orchestrate both transcriptional and non-genomicfunctions in response to estrogens. These pleiotropic andtissue-specific effects are thought to occur because of the differentialexpression of different subtypes of the estrogen receptor (ERα and ERβ)and their co-regulators. Moggs, et al., Estrogen receptors:Orchestrators of pleiotropic cellular responses, FAIBO Report, 2001 Sep.15; 2(9): 775-781. There is intricate complexity to the dynamics ofER-mediated transcription. Id. In addition, estrogen receptors alsoappear to have a direct effect on cytosolic signaling under somecircumstances. Id.

An extensive amount of pharmaceutical research has been directed toidentifying compounds that block the estrogen receptor and shut downundesired actions of the receptor while sometimes trying to maintain thebeneficial effects of the receptor. Other efforts have been directed totrying to completely shut down all estrogen receptor activity, to treatpotentially life-threatening diseases where it is more important toblock all activity than preserve certain beneficial effects.

In June 2011, Aragon Pharmaceuticals disclosed benzopyran derivativesand acolbifene analogs for treatment of tamoxifen-resistant breastcancer (see WO2011/156518, U.S. Pat. Nos. 8,455,534 and 8,299,112).Aragon became Seragon in 2013, and was purchased by Genentech in 2014.See also U.S. Pat. Nos. 9,078,871; 8,853,423; 8,703,810 andUS2015/0005286.

Genentech disclosed a series of tetrahydro-pyrido[3,4-b]indol-1-ylcompounds with estrogen receptor modulation activity in US2016/0175289and US2015/0258080. Genentech is now developing Brilanstrant (GDC-0810)for the treatment of locally advanced or metastatic estrogenic receptorpositive breast cancer.

Genentech, Inc. also disclosed a series of compounds with a moietydescribed as a SERMF (selective estrogen receptor modulator fragment) inUS 2016/0304450 for the treatment of ER-related diseases.

In US 2016/0347742, Genentech disclosed chromene-, thiochromene-,dihydroquinoline-, and naphthalene-based compounds and theirpharmaceutical compositions for the treatment of estrogen-mediateddiseases, including but not limited to breast cancer, uterine cancer,and endometrial cancer. Genentech described chromene-based compoundswith azetidine functionality in US 2016/0090377 and US 2016/0367526,claiming priority from WO2014/205136. These compounds, with a fluorinesubstituent on the azetidine ring, were active in breast cancer, ovariancancer, and uterine cancer cell lines. Genentech disclosed additionalcompounds with fluorine-substituted azetidine moieties on chromene ringsin US 2016/0090378 and US 2016/0175284.

GlaxoSmithKline PLC disclosed a series of benzothiophene analogs, someof which are substituted with short polyethylene glycol basic chains,for the treatment of estrogen receptor-mediated conditions in US2016/0368911.

Eli Lilly and Company disclosed benzothiophene compounds and theirpharmaceutical compositions in U.S. Pat. No. 6,403,614 for the treatmentof postmenopausal syndrome and related estrogen-mediated diseasesincluding cancer. Novartis International AG also disclosed benzothiphenederivatives as SERDs (selective estrogen receptor degraders) for thetreatment of diseases indicated by estrogen dysfunction in WO2014/130310.

Fulvestrant, a complete estrogen receptor antagonist with no agonistactivity, was disclosed by Imperial Chemical Industries (ICI) in U.S.Pat. No. 4,659,516 and is sold by Astra Zeneca under the name Faslodex.It is indicated for the treatment of hormone receptor positivemetastatic breast cancer in post-menopausal women with diseaseprogression following anti-estrogen therapy. Fulvestrant has limitedwater solubility and requires monthly intramuscular (IM) injections.Fulvestrant's aqueous insolubility creates a challenge to achieve andmaintain efficacious serum concentrations.

An example of a selective estrogen receptor modulator (SERMs) which actas antagonists or agonists in a gene-specific and tissue-specificfashion is tamoxifen, initially sold by AstraZeneca under the nameNolvadex. Tamoxifen was also disclosed by ICI in U.S. Pat. No.4,659,516, (see also U.S. Pat. Nos. 6,774,122 and 7,456,160).AstraZeneca is currently developing AZD9496, a novel, oral selectiveestrogen receptor downregulator in patients with estrogen receptorpositive breast cancer (WO 2014/191726).

Aromatase inhibitors which block the production of estrogen andtherefore block ER-dependent growth include letrozole, anastrozole, andexemestane.

A number of SERDs, SERMs, and aromatase inhibitors have been disclosed.The SERM raloxifene was disclosed by Eli Lilly in 1981 (U.S. Pat. Nos.4,418,068; 5,478,847; 5,393,763; and 5,457,117) for prevention of breastcancer and treatment of osteoporosis.

Additional anti-estrogenic compounds are disclosed in WO 2012/084711; WO2002/013802; WO 2002/004418; WO 2002/003992; WO 2002/003991; WO2002/003990; WO 2002/003989; WO 2002/003988; WO 2002/003986; WO2002/003977; WO 2002/003976; WO 2002/003975; WO 2006/078834; U.S. Pat.No. 6,821,989; US 2002/0128276; U.S. Pat. No. 6,777,424; US2002/0016340; U.S. Pat. No. 6,326,392; U.S. Pat. No. 6,756,401; US2002/0013327; U.S. Pat. No. 6,512,002; U.S. Pat. No. 6,632,834; US2001/0056099; U.S. Pat. No. 6,583,170; U.S. Pat. No. 6,479,535; WO1999/024027; U.S. Pat. No. 6,005,102; EP 0802184; U.S. Pat. No.5,998,402; U.S. Pat. No. 5,780,497 and U.S. Pat. No. 5,880,137.

Additional estrogen receptor inhibitors were published by Xiong, et.al., “Novel Selective Estrogen Receptor Downregulators (SERDs) DevelopedAgainst Treatment-Resistant Breast Cancer (J. Med. Chem, Jan. 24, 2017web release). Examples of such selective estrogen receptordownregulators and their biological activities were provided at the Apr.16, 2016 American Associate for Cancer Research (AARC) Conference in aposter presentation by Lauren M. Gutgesell et. al. titled “Estrogenreceptor ligands and their responses in de novo and tamoxifen resistantcell models.” Additional examples in the series of SERDs were describedin the oral presentation and power-point presented by Dr. Thatcher atthe 252^(nd) ACS National Meeting in Philadelphia, Pa. on Aug. 21, 2016.

In light of the role estrogen receptors play in a range of humandisease, including breast tumors and breast cancer, it would be usefulto have additional compounds that are useful to treat these disorders.

SUMMARY OF THE INVENTION

It has been discovered that a compound of Formula I, Formula II, FormulaIII, or Formula IV or a pharmaceutically acceptable salt thereof isuseful to treat an estrogen-related disorder when administered in aneffective amount to treat a host, typically a human, optionally in apharmaceutically acceptable carrier.

In one aspect of the present invention, a compound of Formula I isprovided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug, optionally in a pharmaceutically acceptable carrier to form apharmaceutically acceptable composition thereof;

wherein A is:

m is 0, 1, or 2;

o is 0, 1, 2, 3, 4, or 5 (and typically 1, 2, or 3);

Z is selected from —O—, —C(R³)₂—, —CHR³—, —CH₂—, —CHF—, —CF₂—, and —S—;

each R¹ is independently selected from C₁-C₃alkyl (for example methyl),halogen (for example F), and C₁-C₃haloalkyl;

R² is selected from 4-6 membered heterocycle, optionally substitutedwith one, two, or three groups (and typically one group) independentlyselected from R⁴;

or R² is selected from —NH₂, —NH(C₁-C₃alkyl or C₂-C₃haloalkyl), and—N((independently)C₁-C₃alkyl or C₂-C₃haloalkyl)₂;

R³ is independently selected from —H, —F, —Cl, —Br, —CH₃, —CH₂F, —CHF₂,and —CF₃;

R⁴ and R⁵ are independently selected from hydrogen, halogen, C₁-C₃alkyl,and C₁-C₃haloalkyl;

or R⁴ is selected from hydrogen, halogen (for example F), C₁-C₃alkyl,C₁-C₃haloalkyl, —COOH, —COOC₁-C₁₂alkyl, —CONH₂, —CON(H)alkyl, and—CON(alkyl)₂.

In an alternative embodiment of Formula I, R² is selected frommonocyclic 7-8 membered heterocycle optionally substituted with one,two, or three groups (and typically one group) independently selectedfrom R⁴.

In another alternative embodiment of Formula I, R² is selected from 6-12membered bicyclic or bridged heterocycle optionally substituted withone, two, or three groups (and typically one group) independentlyselected from R⁴.

In another alternative embodiment of Formula I, R² is hydroxyl, alkoxy,—NH—(CH₂)_(n1)—NH₂, —NH—(CH₂)_(n1)—NH(C₁-C₁₂alkyl or C₂-C₁₂haloalkyl),—NH—(CH₂)_(n1)—N((independently)C₁-C₁₂alkyl or C₂-C₁₂haloalkyl),—NHC₄-C₁₂alkyl, or N(C₁-C₁₂alkyl)₂, wherein n1 is 2, 3, 4, 5, or 6.

In another alternative embodiment of Formula I, two R⁴ groups on thesame carbon atom are optionally combined together to forma

group, wherein n3 is 1, 2, 3, 4, or 5. In one embodiment the

is next to a nitrogen atom and R² is an amide or lactam.

In one embodiment C₁-C₃alkyl is cycloalkyl.

In one embodiment C₄-C₁₂alkyl is C₄-C₁₀alkyl.

In one embodiment C₄-C₁₂alkyl is C₄-C₈alkyl.

In one embodiment C₄-C₁₂alkyl is C₄-C₆alkyl.

In one embodiment C₄-C₁₂alkyl is C₆-C₁₀alkyl.

In one embodiment C₄-C₁₂alkyl is C₆-C₈alkyl.

In one embodiment C₄-C₁₂alkyl is a 4, 5, 6, 7, 8, 9, 10, 11, or 12carbon alkyl.

In one embodiment C₁-C₁₂alkyl is C₄-C₁₀alkyl.

In one embodiment C₁-C₁₂alkyl is C₄-C₈alkyl.

In one embodiment C₁-C₁₂alkyl is C₄-C₆alkyl.

In one embodiment C₁-C₁₂alkyl is C₆-C₁₀alkyl.

In one embodiment C₁-C₁₂alkyl is C₆-C₈alkyl.

In one embodiment C₁-C₁₂alkyl is a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or12 carbon alkyl.

In one embodiment n is 2.

In one embodiment n1 is 3.

In one embodiment n1 is 4.

In one embodiment n1 is 5.

In one embodiment n1 is 6.

In one aspect of the present invention, a compound of Formula II isprovided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug, optionally in a pharmaceutically acceptable carrier to form apharmaceutically acceptable composition thereof;

wherein

X is

m is 0, 1, or 2;

n is 1, 2, or 3;

o is 0, 1, 2, 3, 4, or 5 (and typically 1, 2 or 3);

Z is selected from —O—, —C(R³)₂—, —CHR³—, —CH₂—, —CHF—, —CF₂—, and —S—;

each R¹ is independently selected from C₁-C₃alkyl (for example methyl),halogen (for example F), and C₁-C₃haloalkyl (for example F substitutedalkyl);

R² is selected from 4-6 membered heterocycle optionally substituted withone, two, or three groups (and typically one group) independentlyselected from R⁴;

or R² is selected from —NH₂, —NH(C₁-C₃alkyl or C₂-C₃haloalkyl), and—N((independently)C₁-C₃alkyl or C₂-C₃haloalkyl)₂;

R³ is independently selected from —F, —Cl, —Br, —CH₃, —CH₂F, —CHF₂, and—CF₃;

R⁴ and R⁵ are independently selected from hydrogen, halogen (for exampleF), C₁-C₃alkyl, and C₁-C₃haloalkyl;

or R⁴ is selected from hydrogen, halogen (for example F), C₁-C₃alkyl,C₁-C₃haloalkyl, —COOH, —COOC₁-C₁₂alkyl, —CONH₂, —CON(H)alkyl, and—CON(alkyl)₂.

In an alternative embodiment of Formula II, R² is selected frommonocyclic 7-8 membered heterocycle optionally substituted with one,two, or three groups (and typically one group) independently selectedfrom R⁴.

In another alternative embodiment of Formula II, R² is selected from6-12 membered bicyclic or bridged heterocycle optionally substitutedwith one, two, or three groups (and typically one group) independentlyselected from R⁴.

In another alternative embodiment of Formula II, R² is hydroxyl, alkoxy,—NH—(CH₂)_(n1)—NH₂, —NH—(CH₂)_(n1)—NH(C₁-C₁₂alkyl or C₂-C₁₂haloalkyl),—NH—(CH₂)_(n1)—N((independently)C₁-C₁₂alkyl or C₂-C₁₂haloalkyl)₂,—NHC₄-C₁₂alkyl, or —N(C₁-C₁₂alkyl)₂, wherein n1 is 2, 3, 4, 5, or 6.

In another alternative embodiment of Formula II, two R⁴ groups on thesame carbon atom are optionally combined together to form a

group, wherein n3 is 1, 2, 3, 4, or 5. In one embodiment the

is next to a nitrogen atom and R² is an amide or lactam.

In one embodiment n is 1.

In one embodiment n is 2.

In one embodiment n is 3.

In one aspect of the present invention, a compound of Formula III isprovided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug, optionally in a pharmaceutically acceptable carrier to form apharmaceutically acceptable composition thereof;

wherein:

m is 0, 1, or 2;

n is 1, 2, or 3;

o is 0, 1, 2, 3, 4, or 5;

Y is

Z_(A) and Z_(B) are independently selected from —O—, —C(R³)₂—, —CHR³—,—CH₂—, —CHF—, —CF₂—, and —S—;

each R¹ is independently selected from C₁-C₃alkyl, halogen (for exampleF), and C₁-C₃haloalkyl (for example F substituted alkyl);

R² is selected from 4-6 membered heterocycle optionally substituted withone, two, or three groups (and typically one group) independentlyselected from R⁴;

or R² is selected from —NH₂, —NH(C₁-C₃alkyl or C₂-C₃haloalkyl), and—N((independently)C₁-C₃alkyl or C₂-C₃haloalkyl)₂;

R³ is independently selected from —F, —Cl, —Br, —CH₃, —CH₂F, —CHF₂, and—CF₃; and

R⁴ and R⁵ are independently selected from hydrogen, halogen (for exampleF), C₁-C₃alkyl, and C₁-C₃haloalkyl;

or R⁴ is selected from hydrogen, halogen (for example F), C₁-C₃alkyl,C₁-C₃haloalkyl, —COOH, —COOC₁-C₁₂alkyl, —CONH₂, —CON(H)alkyl, and—CON(alkyl)₂.

In an alternative embodiment of Formula III, R² is selected frommonocyclic 7-8 membered heterocycle optionally substituted with one,two, or three groups (and typically one group) independently selectedfrom R⁴.

In another alternative embodiment of Formula III, R² is selected from6-12 membered bicyclic or bridged heterocycle optionally substitutedwith one, two, or three groups (and typically one group) independentlyselected from R⁴.

In another alternative embodiment of Formula III, R² is hydroxyl,alkoxy, —NH—(CH₂)_(n1)—NH₂, —NH—(CH₂)_(n1)—NH(C₁-C₁₂alkyl orC₂-C₁₂haloalkyl), —NH—(CH₂)_(n1)—N((independently)C₁-C₁₂alkyl orC₂-C₁₂haloalkyl)₂, —NHC₄-C₁₂alkyl, or —N(C₁-C₁₂alkyl)₂, wherein n1 is 2,3, 4, 5, or 6.

In another alternative embodiment of Formula III, two R⁴ groups on thesame carbon atom are optionally combined together to form a

group, wherein n3 is 1, 2, 3, 4, or 5. In one embodiment the

is next to a nitrogen atom and R² is an amide or lactam.

In one aspect of the present invention, a compound of Formula IV isprovided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug, optionally in a pharmaceutically acceptable carrier to form apharmaceutically acceptable composition thereof;

wherein:

R⁷ is a 4, 5, 6, 7, 8, 9, or 10 membered heterocycle;

o is independently 0, 1, 2, 3, 4, or 5;

Z is selected from —O—, —C(R³)₂—, —CHR³—, —CH₂—, —CHF—, —CF₂—, and —S—;

each R¹ is independently selected from C₁-C₃alkyl, halogen, andC₁-C₃haloalkyl; and

R³ is independently selected from —F, —Cl, —Br, —CH₃, —CH₂F, —CHF₂, and—CF₃.

In one optional embodiment R⁷ is substituted with oxo.

In another optional embodiment R⁷ is substituted with 1, 2, or 3 groupsselected from R⁴, wherein, two R⁴ groups on the same carbon atom areoptionally combined together to form a

group, wherein n3 is 1, 2, 3, 4, or 5. In one embodiment the

is next to a nitrogen atom and R⁷ is an amide or lactam.

In one embodiment, the compound of Formula IV is selected from:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug, optionally in a pharmaceutically acceptable carrier to form apharmaceutically acceptable composition thereof.

In certain embodiments, the estrogen-related disorder (for example, atumor or cancer) is selected from breast, ovarian, endometrial, kidney,and uterine cancer. In another embodiment the disorder is metastaticendocrine therapy resistant breast cancer. In some embodiments, thecompound is used following chemotherapy or radiation treatment to avoidrecurrence, or instead of chemotherapy or radiation as a primarytreatment.

In one aspect, a compound of Formula I, II, III, or IV or itspharmaceutically acceptable salt or prodrug, can be used to treat ahormone-related cancer or tumor that has metastasized to the brain, boneor other organ. In one embodiment of this aspect, the hormone-relatedcancer is estrogen mediated. In another embodiment, the estrogenmediated cancer is selected from breast, uterine, ovarian andendometrial. In other embodiments, a compound of the present inventionor its pharmaceutically acceptable salt or prodrug, can be used toprevent a hormone-related cancer or tumor from metastasizing to thebrain, bone or other organ, including a hormone-related cancer that isestrogen mediated, for example, breast, uterine, ovarian or endometrial.

In one aspect of the present invention the compound of Formula I,Formula II, Formula III, or Formula IV is administered in combinationwith a compound of Formula V. The compound of Formula V is selectedfrom:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug, optionally in a pharmaceutically acceptable carrier to form apharmaceutically acceptable composition thereof;

wherein:

each Q is independently CH or N;

each R¹¹ is independently aryl, alkyl, or cycloalkyl, wherein two R¹¹groups on adjacent ring atoms or on the same ring atom together with thering atom(s) to which they are attached optionally form a 3-8-memberedcycle;

yl is 0, 1, 2, or 3;

R¹² is -(alkylene)_(m1)-heterocycle, -(alkylene)_(m1)-heteroaryl,-(alkylene)_(m1)-NR¹³R¹⁴, -(alkylene)_(m1)-C(O)—NR¹³R¹⁴,-(alkylene)_(m1)-C(O)—O-alkyl, -(alkylene)_(m1)-O—R¹⁵,-(alkylene)_(m1)-S(O)_(n2)—R¹⁵, or -(alkylene)_(m1)-S(O)_(n2)—NR¹³R¹⁴any of which may be optionally independently substituted with one ormore R^(x) groups as allowed by valence;

m1 is 0 or 1;

n2 is 1 or 2;

R¹³ and R¹⁴ at each occurrence are independently:

-   -   (i) hydrogen or    -   (ii) alkyl, cycloalkyl, heterocycle, aryl, heteroaryl,        cycloalkylalkyl, alkyl-heterocycle, arylalkyl, or        heteroarylalkyl, or R¹³ and R¹⁴ together with the nitrogen atom        to which they are attached may combine to form a heterocycle        ring;

R¹⁵ is:

-   -   (i) hydrogen or    -   (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl,        heteroaryl, cycloalkylalkyl, alkyl-heterocycle, arylalkyl, or        heteroarylalkyl; and

R^(x) at each occurrence is independently, halo, cyano, nitro, alkyl,haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle,aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, oralkyl-heterocycle.

In one embodiment the compound of Formula V is selected from:

The above compounds and several other compounds of Formula V aredisclosed in U.S. Pat. No. 8,598,197; U.S. Pat. No. 8,598,186; U.S. Pat.No. 8,691,830; U.S. Pat. No. 8,829,012; U.S. Pat. No. 8,822,683; U.S.Pat. No. 9,102,682; U.S. Pat. No. 9,499,564; U.S. Pat. No. 9,527,857;and U.S. Pat. No. 9,481,691.

The present invention thus includes at least the following features:

(a) a compound of Formula I, II, III, or IV as described herein, or apharmaceutically acceptable salt or prodrug thereof;

(b) a compound of Formula I, II, III, or IV as described herein, or apharmaceutically acceptable salt or prodrug thereof that is useful inthe treatment or prevention of an estrogen-related disorder, includingwithout limitation a tumor or cancer;

(c) use of a compound of Formula I, II, III, or IV as described herein,or a pharmaceutically acceptable salt or prodrug thereof in themanufacture of a medicament for the treatment or prevention of anestrogen-related disorder, including but not limited to a tumor orcancer;

(d) a method for manufacturing a medicament for the therapeutic use totreat or prevent a disorder of abnormal cellular proliferation includingbut not limited to a tumor or cancer, characterized in that a compoundof Formula I, II, III, or IV or its salt or prodrug as described hereinis used in the manufacture;

(e) a method for manufacturing a medicament for the therapeutic use totreat or prevent an estrogen-related disorder, including but not limitedto a tumor or cancer, characterized in that a compound of Formula I, II,III, or IV or its salt or prodrug as described herein is used in themanufacture;

(f) a method of treating or preventing an estrogen-related disorder,including but not limited to a tumor or cancer, comprising administeringto a subject in need thereof a therapeutically effective amount of acompound selected from Formula I, II, III, or IV or its pharmaceuticallyacceptable salt or prodrug thereof, optionally in a pharmaceuticallyacceptable carrier;

(g) a compound of Formula I, II, III, or IV as described herein or itspharmaceutically acceptable salt or prodrug for use in the treatment orprevention of breast, kidney, uterine, ovarian or endometrial cancer;

(h) use of a compound of Formula I, II, III, or IV as described hereinor a pharmaceutically acceptable salt or prodrug thereof in themanufacture of a medicament for the treatment or prevention of breast,kidney, uterine, ovarian or endometrial cancer;

(i) a method for manufacturing a medicament for the therapeutic use intreating or preventing breast, kidney, uterine, ovarian or endometrialcancer, characterized in that a compound of Formula I, II, III, or IV asdescribed herein or its pharmaceutically acceptable salt or prodrug isused in the manufacture;

(j) a method of treating or preventing breast, kidney, uterine, ovarianor endometrial cancer, comprising administering to a subject in needthereof a therapeutically effective amount of a compound selected fromFormula I, II, III, or IV or its pharmaceutically acceptable salt orprodrug thereof, optionally in a pharmaceutically acceptable carrier;

(k) a compound of Formula I, II, III, or IV as described herein or apharmaceutically acceptable salt or prodrug thereof for use in thetreatment or prevention of hormone receptor positive metastatic breastcancer;

(l) use of a compound of Formula I, II, III, or IV as described hereinor a pharmaceutically acceptable salt or prodrug thereof in themanufacture of a medicament for the treatment or prevention of a hormonereceptor positive metastatic breast cancer tumor;

(m) a method for manufacturing a medicament for treatment or preventionof a hormone receptor positive metastatic breast cancer, characterizedin that a compound of Formula I, II, III, or IV as described herein orits pharmaceutically acceptable salt or prodrug is used in themanufacture;

(n) a method of treating or preventing hormone receptor positivemetastatic breast cancer, comprising administering to a subject in needthereof a therapeutically effective amount of a compound selected fromFormula I, II, III, or IV or its pharmaceutically acceptable salt orprodrug thereof, optionally in a pharmaceutically acceptable carrier;

(o) a compound of Formula I, II, III, or IV as described herein or apharmaceutically acceptable salt or prodrug thereof for use to treat orprevent bone loss, including osteoporosis;

(p) use of a compound of Formula I, II, III, or IV as described hereinor a pharmaceutically acceptable salt or prodrug thereof in themanufacture of a medicament for the treatment or prevention of boneloss, including osteoporosis;

(q) a method for manufacturing a medicament for use to treat or preventbone loss, including osteoporosis, characterized in that a compound ofFormula I, II, III, or IV as described herein is used in themanufacture;

(r) a method of treating or preventing bone loss, includingosteoporosis, comprising administering to a subject in need thereof atherapeutically effective amount of a compound selected from Formula I,II, III, or IV or its pharmaceutically acceptable salt or prodrugthereof, optionally in a pharmaceutically acceptable carrier;

(s) a pharmaceutical formulation comprising an effective treatment orprevention amount of a compound of a compound of Formula I, II, III, orIV as described herein or a pharmaceutically acceptable salt or prodrugthereof together with a pharmaceutically acceptable carrier or diluent;

(t) a compound of Formula I, II, III, or IV as described herein, or itspharmaceutically acceptable salt or prodrug as a mixture of enantiomersor diastereomers (as relevant), including as a racemate;

(u) a compound of Formula I, II, III, or IV of the present invention asdescribed herein in enantiomerically or diastereomerically (as relevant)enriched form, including as an isolated enantiomer or diastereomer(i.e., greater than 85, 90, 95, 97 or 99% pure);

(v) a process for the preparation of a therapeutic product that containan effective amount of a compound of Formula I, II, III, or IV asdescribed herein, or its pharmaceutically acceptable salt or prodrug:

(w) a compound of Formula I, II, III, or IV as described hereinisotopically substituted with deuterium; and

(x) an isotopic derivative of a compound of Formula I, II, III, or IV asdescribed herein.

(y) a pharmaceutically acceptable composition as described herein,comprising a compound of Formula I, II, III, or IV, or itspharmaceutically acceptable salt or prodrug thereof, and a compound ofFormula V or its pharmaceutically acceptable salt or prodrug thereof,

(z) a pharmaceutically acceptable composition as described herein,comprising a compound of Formula I, II, III, or IV, or itspharmaceutically acceptable salt or prodrug thereof, and a compound ofFormula V or its pharmaceutically acceptable salt or prodrug thereof,for use in the treatment or prevention of an estrogen-related disorder,including without limitation a tumor or cancer;

(aa) use of a pharmaceutically acceptable composition as describedherein, comprising a compound of Formula I, II, III, or IV, or itspharmaceutically acceptable salt or prodrug thereof, and a compound ofFormula V or its pharmaceutically acceptable salt or prodrug thereof, inthe manufacture of a medicament for the treatment or prevention of anestrogen-related disorder, including but not limited to a tumor orcancer;

(bb) a method for manufacturing a medicament for the therapeutic use oftreating or preventing an estrogen-related disorder, including but notlimited to a tumor or cancer, characterized in that a compound ofFormula I, II, III, or IV or its pharmaceutically acceptable salt orprodrug thereof and a compound of Formula V or its pharmaceuticallyacceptable salt or prodrug thereof is used in the manufacture;

(cc) a method of treating or preventing an estrogen-related disorder,including but not limited to a tumor or cancer, comprising administeringto a subject in need thereof a therapeutically effective amount of acompound selected from Formula I, II, III, or IV or its pharmaceuticallyacceptable salt or prodrug thereof and a therapeutically effectiveamount of a compound of Formula V or its pharmaceutically acceptablesalt or prodrug thereof, optionally in a pharmaceutically acceptablecarrier;

(dd) a pharmaceutically acceptable composition as described herein,comprising a compound of Formula I, II, III, or IV, or itspharmaceutically acceptable salt or prodrug thereof, and a compound ofFormula V or its pharmaceutically acceptable salt or prodrug thereof,for use in the treatment or prevention of breast, kidney, uterine,ovarian, or endometrial cancer;

(ee) use of a pharmaceutically acceptable composition as describedherein, comprising a compound of Formula I, II, III, or IV, or itspharmaceutically acceptable salt or prodrug thereof, and a compound ofFormula V or its pharmaceutically acceptable salt or prodrug thereof, inthe manufacture of a medicament for the treatment or prevention ofbreast, kidney, uterine, ovarian, or endometrial cancer;

(ff) a method for manufacturing a medicament for the therapeutic use oftreating or preventing breast, kidney, uterine, ovarian, or endometrialcancer, characterized in that a compound of Formula I, II, III, or IV orits pharmaceutically acceptable salt or prodrug thereof and a compoundof Formula V or its pharmaceutically acceptable salt or prodrug thereofis used in the manufacture;

(gg) a method of treating or preventing breast, kidney, uterine,ovarian, or endometrial cancer, comprising administering to a subject inneed thereof a therapeutically effective amount of a compound selectedfrom Formula I, II, III, or IV or its pharmaceutically acceptable saltor prodrug thereof and a therapeutically effective amount of a compoundof Formula V or its pharmaceutically acceptable salt or prodrug thereof,optionally in a pharmaceutically acceptable carrier;

(hh) a pharmaceutically acceptable composition as described herein,comprising a compound of Formula I, II, III, or IV, or itspharmaceutically acceptable salt or prodrug thereof, and a compound ofFormula V or its pharmaceutically acceptable salt or prodrug thereof,for use in the treatment or prevention of hormone receptor positivemetastatic breast cancer;

(ii) use of a pharmaceutically acceptable composition as describedherein, comprising a compound of Formula I, II, III, or IV, or itspharmaceutically acceptable salt or prodrug thereof, and a compound ofFormula V or its pharmaceutically acceptable salt or prodrug thereof, inthe manufacture of a medicament for the treatment or prevention ofhormone receptor positive metastatic breast cancer;

(jj) a method for manufacturing a medicament for the therapeutic use oftreating or preventing hormone receptor positive metastatic breastcancer, characterized in that a compound of Formula I, II, III, or IV orits pharmaceutically acceptable salt or prodrug thereof and a compoundof Formula V or its pharmaceutically acceptable salt or prodrug thereofis used in the manufacture;

(kk) a method of treating or preventing a hormone receptor positivemetastatic breast cancer, comprising administering to a subject in needthereof a therapeutically effective amount of a compound selected fromFormula I, II, III, or IV or its pharmaceutically acceptable salt orprodrug thereof and a therapeutically effective amount of a compound ofFormula V or its pharmaceutically acceptable salt or prodrug thereof,optionally in a pharmaceutically acceptable carrier;

(ll) a pharmaceutically acceptable composition as described herein,comprising a compound of Formula I, II, III, or IV, or itspharmaceutically acceptable salt or prodrug thereof, and a compound ofFormula V or its pharmaceutically acceptable salt or prodrug thereof,for use in the treatment or prevention of bone loss, includingosteoporosis;

(mm) use of a pharmaceutically acceptable composition as describedherein, comprising a compound of Formula I, II, III, or IV, or itspharmaceutically acceptable salt or prodrug thereof, and a compound ofFormula V or its pharmaceutically acceptable salt or prodrug thereof, inthe manufacture of a medicament for the treatment or prevention of boneloss, including osteoporosis;

(nn) a method for manufacturing a medicament for the therapeutic use oftreating or preventing bone loss, including osteoporosis, characterizedin that a compound of Formula I, II, III, or IV or its pharmaceuticallyacceptable salt or prodrug thereof and a compound of Formula V or itspharmaceutically acceptable salt or prodrug thereof is used in themanufacture;

(oo) a method of treating or preventing bone loss, includingosteoporosis, comprising administering to a subject in need thereof atherapeutically effective amount of a compound selected from Formula I,II, III, or IV or its pharmaceutically acceptable salt or prodrugthereof and a therapeutically effective amount of a compound of FormulaV or its pharmaceutically acceptable salt or prodrug thereof, optionallyin a pharmaceutically acceptable carrier;

(pp) a pharmaceutically acceptable composition as described herein,comprising a compound of Formula I, II, III, or IV, or itspharmaceutically acceptable salt or prodrug thereof, and a compound ofFormula V or its pharmaceutically acceptable salt or prodrug thereof,for use in the treatment or prevention of bone loss, includingosteoporosis;

(qq) use of a pharmaceutically acceptable composition as describedherein, comprising a compound of Formula I, II, III, or IV, or itspharmaceutically acceptable salt or prodrug thereof, and a compound ofFormula V or its pharmaceutically acceptable salt or prodrug thereof, inthe manufacture of a medicament for the treatment or prevention of boneloss, including osteoporosis;

(rr) a method for manufacturing a medicament for the therapeutic use oftreating or preventing bone loss, including osteoporosis, characterizedin that a compound of Formula I, II, III, or IV or its pharmaceuticallyacceptable salt or prodrug thereof and a compound of Formula V or itspharmaceutically acceptable salt or prodrug thereof is used in themanufacture;

(ss) a method of treating or preventing bone loss, includingosteoporosis, comprising administering to a subject in need thereof atherapeutically effective amount of a compound selected from Formula I,II, III, or IV or its pharmaceutically acceptable salt or prodrugthereof and a therapeutically effective amount of a compound of FormulaV or its pharmaceutically acceptable salt or prodrug thereof, optionallyin a pharmaceutically acceptable carrier;

(tt) a process for the preparation of a therapeutic product thatcontains an effective amount of a compound of Formula I, II, III, or IVor its pharmaceutically acceptable salt or prodrug thereof and aneffective amount of a compound of Formula V or its pharmaceuticallyacceptable salt or prodrug thereof;

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of estrogen receptor activity measured in the HumanEstrogen Receptor alpha Reporter Assay described in Example 3. They-axis is estrogen receptor activity measured by percent. The x-axis isconcentration of the SERD measured in Molar units and presented onlogarithmic scale. The three compounds tested were Compound 100,RAD1901, and AZD9496.

FIG. 2 is a graph of estrogen receptor activity measured in the EstrogenReceptor (ER) degradation assay described in Example 4. The y-axis isestrogen receptor response measured by percent. The x-axis isconcentration of the SERD measured in Molar units and presented onlogarithmic scale. The three compounds tested were Compound 100,RAD1901, and AZD9496.

FIG. 3 is a graph of estrogen receptor remaining measured in theEstrogen Receptor (ER) degradation assay described in Example 4. They-axis is estrogen receptor activity measured by percent. The x-axis isconcentration of the SERD measured in Molar units and presented onlogarithmic scale. The four compounds tested were Compound 100, Compound117, Compound 118, and Compound 119. The IC₅₀ values corresponding tothis dose response curves are provided in Table 3.

FIG. 4 is a graph of estrogen receptor remaining measured in theEstrogen Receptor (ER) degradation assay described in Example 4. They-axis is estrogen receptor activity measured by percent. The x-axis isconcentration of the SERD measured in Molar units and presented onlogarithmic scale. The four compounds tested were Compound 120, Compound123, Compound 124, and Compound 126. The IC₅₀ values corresponding tothis dose response curves are provided in Table 3.

FIG. 5 is a graph of estrogen receptor remaining measured in theEstrogen Receptor (ER) degradation assay described in Example 4. They-axis is estrogen receptor activity measured by percent. The x-axis isconcentration of the SERD measured in Molar units and presented onlogarithmic scale. The four compounds tested were Compound 101, Compound102, Compound 107, and RAD-1901. The IC₅₀ values corresponding to thisdose response curves are provided in Table 3.

FIG. 6 is a graph of estrogen receptor remaining measured in theEstrogen Receptor (ER) degradation assay described in Example 4. They-axis is estrogen receptor activity measured by percent. The x-axis isconcentration of the SERD measured in Molar units and presented onlogarithmic scale. The four compounds tested were Compound 103, Compound105, Compound 106, and Compound 108. The IC₅₀ values corresponding tothis dose response curves are provided in Table 3.

FIG. 7 is a graph of estrogen receptor remaining measured in theEstrogen Receptor (ER) degradation assay described in Example 4. They-axis is estrogen receptor activity measured by percent. The x-axis isconcentration of the SERD measured in Molar units and presented onlogarithmic scale. The four compounds tested were Compound 109, Compound110, Compound 111, and Compound 112. The IC₅₀ values corresponding tothis dose response curves are provided in Table 3.

FIG. 8 is a graph of estrogen receptor remaining measured in theEstrogen Receptor (ER) degradation assay described in Example 4. They-axis is estrogen receptor activity measured by percent. The x-axis isconcentration of the SERD measured in Molar units and presented onlogarithmic scale. The five compounds tested were Compound 104, Compound113, Compound 114, Compound 115, and Compound 116. The IC₅₀ valuescorresponding to this dose response curves are provided in Table 3.

FIG. 9 is a graph of estrogen receptor activity measured in the HumanEstrogen Receptor alpha Reporter Assay described in Example 3. They-axis is estrogen receptor activity measured by percent. The x-axis isconcentration of the SERD measured in Molar units and presented onlogarithmic scale. The four compounds tested were Compound 100, Compound117, Compound 118, and Compound 119. The IC₅₀ values corresponding tothis dose response curves are provided in Table 3.

FIG. 10 is a graph of estrogen receptor activity measured in the HumanEstrogen Receptor alpha Reporter Assay described in Example 3. They-axis is estrogen receptor activity measured by percent. The x-axis isconcentration of the SERD measured in Molar units and presented onlogarithmic scale. The four compounds tested were Compound 120, Compound123, Compound 124, and Compound 126. The IC₅₀ values corresponding tothis dose response curves are provided in Table 3.

FIG. 11 is a graph of estrogen receptor activity measured in the HumanEstrogen Receptor alpha Reporter Assay described in Example 3. They-axis is estrogen receptor activity measured by percent. The x-axis isconcentration of the SERD measured in Molar units and presented onlogarithmic scale. The four compounds tested were Compound 101, Compound102, Compound 107, and RAD-1901. The IC₅₀ values corresponding to thisdose response curves are provided in Table 3.

FIG. 12 is a graph of estrogen receptor activity measured in the HumanEstrogen Receptor alpha Reporter Assay described in Example 3. They-axis is estrogen receptor activity measured by percent. The x-axis isconcentration of the SERD measured in Molar units and presented onlogarithmic scale. The four compounds tested were Compound 103, Compound105, Compound 106, Compound 108, and Compound 109. The IC₅₀ valuescorresponding to this dose response curves are provided in Table 3.

FIG. 13 is a graph of estrogen receptor activity measured in the HumanEstrogen Receptor alpha Reporter Assay described in Example 3. They-axis is estrogen receptor activity measured by percent. The x-axis isconcentration of the SERD measured in Molar units and presented onlogarithmic scale. The four compounds tested were Compound 104, Compound110, Compound 111, and Compound 112. The IC₅₀ values corresponding tothis dose response curves are provided in Table 3.

FIG. 14 is a graph of estrogen receptor activity measured in the HumanEstrogen Receptor alpha Reporter Assay described in Example 3. They-axis is estrogen receptor activity measured by percent. The x-axis isconcentration of the SERD measured in Molar units and presented onlogarithmic scale. The four compounds tested were Compound 113, Compound114, Compound 115, and Compound 116. The IC₅₀ values corresponding tothis dose response curves are provided in Table 3.

FIG. 15 depicts a few non-limiting subgenuses of Formula I. In FIG. 15 mis 0, 1, or 2; n is 1, 2, or 3; and each R¹ is independently selectedfrom C₁-C₃alkyl, halogen, and C₁-C₃haloalkyl.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Compounds are described using standard nomenclature. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to whichthis invention belongs.

The compounds of Formula I, II, III, and IV as described herein may beprovided in the form of a racemate, enantiomer, mixture of enantiomers,diastereomer, mixtures of diastereomers, tautomer, N-oxide, an isomersuch as a rotamer, as if each is specifically described, unlessotherwise drawn or a designation is clear from the context herein.

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item. Theterm “or” means “and/or”. Recitation of ranges of values are merelyintended to serve as a shorthand method of referring individually toeach separate value falling within the range, unless otherwise indicatedherein, and each separate value is incorporated into the specificationas if it were individually recited herein. The endpoints of all rangesare included within the range and independently combinable. All methodsdescribed herein can be performed in a suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof examples, or exemplary language (e.g., “such as”), is intended merelyto better illustrate the invention and does not pose a limitation on thescope of the invention unless otherwise claimed. Unless definedotherwise, technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to whichthis invention belongs.

The term “C₁-C₃ alkyl” independently refers to methyl, ethyl, propyl,isopropyl, and cyclopropyl as if each were independently recited.

The term “C₁-C₃ haloalkyl” is C₁-C₃ alkyl wherein any hydrogen can bereplaced independently with fluorine, chlorine, or bromine. The term“C₁-C₃ haloalkyl” includes —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂,—CH₂CF₃, —CHFCF₃, —CF₂CF₃, —CH₂CH₂CH₂F, —CH₂CH₂CHF₂, —CH₂CH₂CF₃,—CH₂CHFCF₃, —CH₂CF₂CF₃, —CHFCF₂CF₃, —CF₂CF₂CF₃, CHFCH₂F, —CHFCHF₂,—CHFCF₃, —CHFCH₂CH₂F, —CHFCH₂CHF₂, —CHFCH₂CF₃, —CHFCHFCF₃, —CHFCF₂CF₃,—CF₂CH₂CH₂F, —CF₂CH₂CHF₂, —CF₂CH₂CF₃, —CF₂CHFCF₃, —CH₂CF₂CHF₂,—CH₂CF₂CH₂F, —CHFCHFCHF₂, —CHFCHFCH₂F, as if each were independentlyrecited. As clear to one of skill in the art, a number of theseembodiments have chiral carbons and thus can exist as enantiomers ordiastereomers. This disclosure covers all possible stereoisomers eitheras mixtures or in enantiomerically enriched form (e.g., at least 80, 85,90, 95, or 98% free of the other isomers).

The term “alkyl” is a branched or straight chain saturated aliphatichydrocarbon group. In one non-limiting embodiment, the alkyl groupcontains from 1 to about 12 carbon atoms, more generally from 1 to about6 carbon atoms or from 1 to about 4 carbon atoms. In one non-limitingembodiment, the alkyl contains from 1 to about 8 carbon atoms. Incertain embodiments, the alkyl is C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅, or C₁-C₆.The specified ranges as used herein indicate an alkyl group having eachmember of the range described as an independent species. For example,the term C₁-C₆ alkyl as used herein indicates a straight or branchedalkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intendedto mean that each of these is described as an independent species. Forexample, the term C₁-C₄ alkyl as used herein indicates a straight orbranched alkyl group having from 1, 2, 3, or 4 carbon atoms and isintended to mean that each of these is described as an independentspecies. Examples of alkyl include, but are not limited to, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl,n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane,3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In analternative embodiment, the alkyl group is optionally substituted. Theterm “Alkyl” also encompasses cycloalkyl or carbocyclic groups. Forexample, when a term is used that includes “alk” then “cycloalkyl” or“carbocyclic” can be considered part of the definition, unlessunambiguously excluded by the context. For example and withoutlimitation, the terms alkyl, alkoxy, haloalkyl, etc. can all beconsidered to include the cyclic forms of alkyl, unless unambiguouslyexcluded by context.

“Halo” or “halogen” means —Cl, —Br, —I or —F (and typically F). Incertain embodiments, “halo” or “halogen” may refers independently to —Clor —F.

“Haloalkyl” is a branched or straight-chain alkyl groups substitutedwith 1 or more halo atoms (typically F), up to the maximum allowablenumber of halogen atoms. Examples of haloalkyl groups include, but arenot limited to, fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.“Perhaloalkyl” means an alkyl group having all hydrogen atoms replacedwith halogen atoms. Examples include but are not limited to,trifluoromethyl and pentafluoroethyl.

The term “heteroaryl” denotes stable aromatic ring systems that containone or more heteroatoms selected from O, N, and S, wherein the ringnitrogen and sulfur atom(s) are optionally oxidized, and nitrogenatom(s) are optionally quarternized. Examples include but are notlimited to, unsaturated 5 to 6 membered heteromonocyclyl groupscontaining 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl,pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, IH-1,2,3-triazolyl,2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclicgroups containing an oxygen atom, for example, pyranyl, 2-furyl,3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic groupscontaining a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.;unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groupscontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example,thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl]. In one embodiment the “heteroaryl” group is a 8, 9,or 10 membered bicyclic ring system. Examples of 8, 9, or 10 memberedbicyclic heteroaryl groups include benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl,indazolyl, and benzotriazolyl.

“Arylalkyl” is an aryl group as defined herein attached through an alkylgroup. Non-limiting examples of arylalkyl groups include:

“Heteroarylalkyl” is a heteroaryl group as defined herein attachedthrough an alkyl group. Non-limiting examples of heteroarylalkyl groupsinclude:

“Aryloxy” is an aryl group as defined herein attached through a —O—linker. Non-limiting examples of aryloxy groups include:

The term “heterocycle”, “heterocyclyl”, or “heterocyclo” includessaturated, and partially saturated heteroatom-containing ring radicals,where the heteroatoms may be selected from nitrogen, sulfur and oxygen(and typically nitrogen). It does not include rings containing —O—O—,—O—S— or —S—S— portions. In one embodiment the “heterocycle” group isoptionally substituted with 1 to 3 substituents that include but are notlimited to, hydroxyl, Boc, halo, haloalkyl, cyano, alkyl, arylalkyl,heteroarylalkyl, oxo, alkoxy, and amino. Examples of heterocycle groupsinclude 3- to 6-membered heteromonocyclic groups containing 1 to 4nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, piperazinyl); saturated 3 to 6-membered heteromonocyclicgroup containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g.morpholinyl); saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g.,thiazolidinyl). Examples of partially saturated heterocycle radicalsinclude but are not limited to, dihydrothienyl, dihydropyranyl,dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated andsaturated heterocycle groups include but are not limited to,pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl,piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl,dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl,dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl,1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,1,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl. The terms “heterocycle”, “heterocyclyl”, and“heterocyclo” are used interchangeably herein. The term “heterocycle”except where excluded by context, includes bicyclic and tricyclicheterocycles. For example 2-azabicyclo[2.1.1]hexane would be considereda 6-membered heterocycle, and 3-azabicyclo[3.2.0]heptane would beconsidered a 7-membered heterocycle.

As used herein the term “bicyclic heterocycle” refers to a heterocycleas defined herein with additional fused rings. Non-limiting examples ofbicyclic heterocycles include:

Unless otherwise drawn or clear from the context, the term “bicyclicheterocycle” includes cis and trans diastereomers. Non-limiting examplesof chiral bicyclic heterocycles include:

As used herein the term “bridged heterocycle” refers to a heterocycle asdefined herein with at least one bridging carbon atom. Non-limitingexamples of bridged heterocycles include:

Heterocycle groups also include radicals where heterocyclic radicals arefused/condensed with aryl radicals: such as unsaturated condensedheterocyclic group containing 1 to 5 nitrogen atoms, for example,indoline, isoindoline, unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturatedcondensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, and saturated, partially unsaturated and unsaturatedcondensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms.

“Pharmaceutically acceptable salt” refers to both acid and base additionsalts.

“Treating” or “treatment” refer to the treatment of a disease ordisorder described herein, in a subject, preferably a human, andincludes:

i. inhibiting a disease or disorder, i.e., arresting its development;

ii. relieving a disease or disorder, i.e., causing regression of thedisorder;

iii. slowing progression of the disorder; and/or

iv. inhibiting, relieving, or slowing progression of one or moresymptoms of the disease or disorder

“Host” refers to a warm-blooded animal such as a mammal, typically ahuman, which is afflicted with one or more diseases and disordersdescribed herein.

A “prodrug” as used herein, means a compound which when administered toa host in vivo is converted into a parent drug. As used herein, the term“parent drug” means any of the presently described chemical compoundsdescribed herein. Prodrugs can be used to achieve any desired effect,including to enhance properties of the parent drug or to improve thepharmaceutic or pharmacokinetic properties of the parent. Prodrugstrategies exist which provide choices in modulating the conditions forin vivo generation of the parent drug, all of which are deemed includedherein. Nonlimiting examples of prodrug strategies include covalentattachment of removable groups, or removable portions of groups, forexample, but not limited to acylation, phosphorylation, phosphonylation,phosphoramidate derivatives, amidation, reduction, oxidation,esterification, alkylation, other carboxy derivatives, sulfoxy orsulfone derivatives, carbonylation or anhydride, among others.

The present invention includes compounds of Formula I, II, III, and IVwith at least one desired isotopic substitution of an atom, at an amountabove the natural abundance of the isotope, i.e., enriched. Isotopes areatoms having the same atomic number but different mass numbers, i.e.,the same number of protons but a different number of neutrons.

The present invention also includes combination treatment andpharmaceutical compositions including compounds of Formula V with atleast one desired isotopic substitution of an atom, at an amount abovethe natural abundance of the isotope, i.e., enriched. Isotopes are atomshaving the same atomic number but different mass numbers, i.e., the samenumber of protons but a different number of neutrons.

Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,fluorine and chlorine such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ¹⁸F,³⁵S, ³⁶Cl, and respectively. In one non-limiting embodiment,isotopically labelled compounds can be used in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F labeled compound may be particularlydesirable for PET or SPECT studies. Isotopically labeled compounds ofthis invention and prodrugs thereof can generally be prepared bycarrying out the procedures disclosed in the schemes or in the examplesand preparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

By way of general example and without limitation, isotopes of hydrogen,for example, deuterium (²H) and tritium (³H) may be used anywhere indescribed structures that achieves the desired result. Alternatively orin addition, isotopes of carbon, e.g., ¹³C and ¹⁴C, may be used.

Isotopic substitutions, for example deuterium substitutions, can bepartial or complete. Partial deuterium substitution means that at leastone hydrogen is substituted with deuterium. In certain embodiments, theisotope is 90, 95 or 99% or more enriched in an isotope at any locationof interest. In one non-limiting embodiment, deuterium is 90, 95 or 99%enriched at a desired location.

In one non-limiting embodiment, the substitution of a hydrogen atom fora deuterium atom can be provided in a compound of Formula I, II, III,IV, V. In one non-limiting embodiment, the substitution of a hydrogenatom for a deuterium atom occurs within a group selected from any of X,Y, A, Z, R¹, R², R³, R⁴, R⁵, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, and R^(x). Forexample, when any of the groups are, or contain for example throughsubstitution, methyl, ethyl, or methoxy, the alkyl residue may bedeuterated (in non-limiting embodiments, CDH₂, CD₂H, CD₃, CH₂CD₃,CD₂CD₃, CHDCH₂D, CH₂CD₃, CHDCHD₂, OCDH₂, OCD₂H, or OCD₃ etc.). Incertain other embodiments, when two substituents are combined to form acycle the unsubstituted carbons may be deuterated.

RAD1901 is a compound of structure

AZD9496 is a compound of structure

Compounds

Benzothiophene based estrogen receptor ligands of the invention includescompounds of Formula I, II, III, or IV, or a pharmaceutically acceptablesalt thereof:

In one embodiment, a compound of Formula I is provided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug, optionally in a pharmaceutically acceptable carrier to form apharmaceutically acceptable composition thereof;

wherein A is:

m is 0, 1, or 2;

o is 0, 1, 2, 3, 4, or 5 (and typically 1, 2 or 3);

Z is selected from —O—, —C(R³)₂—, —CHR³—, —CH₂—, —CHF—, —CF₂—, and —S—;

each R¹ is independently selected from C₁-C₃alkyl, halogen, andC₁-C₃haloalkyl;

R² is selected from 4-6 membered heterocycle optionally substituted withone, two, or three groups (and typically one group) independentlyselected from R⁴; or

R² is selected from —NH₂, —NH(C₁-C₃alkyl or C₂-C₃haloalkyl), and—N((independently)C₁-C₃alkyl or C₂-C₃haloalkyl)₂;

R³ is independently selected from —F, —Cl, —Br, —CH₃, —CH₂F, —CHF₂, and—CF₃; and

R⁴ and R⁵ are independently selected from hydrogen, halogen, C₁-C₃alkyl,and C₁-C₃haloalkyl.

In an alternative embodiment of Formula I, R² is selected frommonocyclic 7-8 membered heterocycle optionally substituted with one,two, or three groups (and typically one group) independently selectedfrom R⁴.

In another alternative embodiment of Formula I, R² is selected from 6-12membered bicyclic or bridged heterocycle optionally substituted withone, two, or three groups (and typically one group) independentlyselected from R⁴.

In another alternative embodiment of Formula I, R² is—NH—(CH₂)_(n1)—NH₂, —NH—(CH₂)_(n1)—NH(C₁-C₁₂alkyl or C₂-C₁₂haloalkyl),—NH—(CH₂)_(n1)—N((independently)C₁-C₁₂alkyl or C₂-C₁₂haloalkyl)₂,—NHC₄-C₁₂alkyl, or N(C₁-C₁₂alkyl)₂, wherein n1 is 2, 3, 4, 5, or 6.

In one embodiment, a compound of Formula II is provided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug, optionally in a pharmaceutically acceptable carrier to form apharmaceutically acceptable composition thereof;

wherein

X is

m is 0, 1, or 2;

n is 1, 2, or 3;

o is 0, 1, 2, 3, 4, or 5 (and typically 1, 2 or 3);

Z is selected from —O—, —C(R³)₂—, —CHR³—, —CH₂—, —CHF—, —CF₂—, and —S—;

each R¹ is independently selected from C₁-C₃alkyl (for example methyl),halogen (for example F), and C₁-C₃haloalkyl (typically F substitutedalkyl);

R² is selected from 4-6 membered heterocycle optionally substituted withone, two, or three groups (and typically one group) independentlyselected from R⁴; or

R² is selected from —NH₂. —NH(C₁-C₃alkyl or C₂-C₃haloalkyl), and—N((independently)C₁-C₃alkyl or C₂-C₃haloalkyl)₂;

R³ is independently selected from —F, —Cl, —Br, —CH₃, —CH₂F, —CHF₂, and—CF₃; and

R⁴ and R⁵ are independently selected from hydrogen, halogen (for exampleF), C₁-C₃alkyl, and C₁-C₃haloalkyl.

In an alternative embodiment of Formula II, R² is selected frommonocyclic 7-8 membered heterocycle optionally substituted with one,two, or three groups (and typically one group) independently selectedfrom R⁴.

In another alternative embodiment of Formula II, R² is selected from6-12 membered bicyclic or bridged heterocycle optionally substitutedwith one, two, or three groups (and typically one group) independentlyselected from R⁴.

In another alternative embodiment of Formula II, R² is—NH—(CH₂)_(n1)—NH₂, —NH—(CH₂)_(n1)—NH(C₁-C₁₂alkyl or C₂-C₁₂haloalkyl),—NH—(CH₂)_(n1)—N((independently)C₁-C₁₂alkyl or C₂-C₁₂haloalkyl)₂,—NHC₄-C₁₂alkyl, or —N(C₁-C₁₂alkyl)₂, wherein n1 is 2, 3, 4, 5, or 6.

In one embodiment, a compound of Formula III is provided:

or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, orprodrug, optionally in a pharmaceutically acceptable carrier to form apharmaceutically acceptable composition thereof;

wherein:

m is 0, 1, or 2;

n is 1, 2, or 3;

o is 0, 1, 2, 3, 4, or 5;

Y is

Z_(A) and Z_(B) are independently selected from —O—, —C(R³)₂—, —CHR³—,—CH₂—, —CHF—, —CF₂—, and —S—;

each R¹ is independently selected from C₁-C₃alkyl, halogen (for exampleF), and C₁-C₃haloalkyl (for example F substituted);

R² is selected from 4-6 membered heterocycle optionally substituted withone, two, or three groups (and typically one group) independentlyselected from R⁴; or

R² is selected from —NH₂, —NH(C₁-C₃alkyl or C₂-C₃haloalkyl), and—N((independently)C₁-C₃alkyl or C₂-C₃haloalkyl)₂;

R³ is independently selected from —F, —Cl, —Br, —CH₃, —CH₂F, —CHF₂, and—CF₃; and

R⁴ and R⁵ are independently selected from hydrogen, halogen (for exampleF), C₁-C₃alkyl, and C₁-C₃haloalkyl.

In an alternative embodiment of Formula III, R² is selected frommonocyclic 7-8 membered heterocycle optionally substituted with one,two, or three groups (and typically one group) independently selectedfrom R⁴.

In another alternative embodiment of Formula III, R² is selected from6-12 membered bicyclic or bridged heterocycle optionally substitutedwith one, two, or three groups (and typically one group) independentlyselected from R⁴.

In another alternative embodiment of Formula III, R² is—NH—(CH₂)_(n1)—NH₂, —NH—(CH₂)_(n1)—NH(C₁-C₁₂alkyl or C₂-C₁₂haloalkyl),—NH—(CH₂)_(n1)—N((independently)C₁-C₁₂alkyl or C₂-C₁₂haloalkyl)₂,—NHC₄-C₁₂alkyl, or —N(C₁-C₁₂alkyl)₂, wherein n1 is 2, 3, 4, 5, or 6.

In one embodiment the compound of Formula I is of Formula I-A:

In one embodiment the compound of Formula I is of Formula I-B:

In one embodiment the compound of Formula I is of Formula I-C:

In one embodiment the compound of Formula I is of Formula I-D:

In one embodiment the compound of Formula I is of Formula I-E:

In one embodiment the compound of Formula I is of Formula I-F:

In one embodiment the compound of Formula I is of Formula I-G:

In one embodiment the compound of Formula I is of Formula I-H:

In one embodiment the compound of Formula I is of Formula I-J:

In one embodiment the compound of Formula I is of Formula I-K:

In one embodiment the compound of Formula I is of Formula I-L:

In one embodiment the compound of Formula II is of Formula II-A:

In one embodiment the compound of Formula II is of Formula II-B:

In one embodiment the compound of Formula I is of Formula II-C:

In one embodiment the compound of Formula II is of Formula II-D:

In one embodiment the compound of Formula II is of Formula II-E:

In one embodiment the compound of Formula II is of Formula II-F:

In one embodiment the compound of Formula II is of Formula II-G:

In one embodiment the compound of Formula II is of Formula II-H:

In one embodiment the compound of Formula II is of Formula II-J:

In one embodiment the compound of Formula II is of Formula II-K:

In one embodiment the compound of Formula II is of Formula II-L:

In one embodiment the compound of Formula III is of Formula III-A:

In one embodiment the compound of Formula III is of Formula III-B:

In one embodiment the compound of Formula III is of Formula III-C:

In one embodiment the compound of Formula III is of Formula III-D:

In one embodiment the compound of Formula III is of Formula III-E:

In one embodiment the compound of Formula III is of Formula III-F:

In one embodiment the compound of Formula III is of Formula III-G:

In one embodiment the compound of Formula III is of Formula III-H:

In one embodiment the compound of Formula III is of Formula III-J:

In one embodiment the compound of Formula III is of Formula III-K:

In one embodiment the compound of Formula III is of Formula III-L:

In one embodiment the compound of Formula I is:

In one embodiment the compound of Formula II is:

In one embodiment the compound of Formula V is:

or a pharmaceutically acceptable salt thereof.

In one embodiment the compound of Formula V is:

or a pharmaceutically acceptable salt thereof.

In one embodiment the compound of Formula V is:

or a pharmaceutically acceptable salt thereof.

In one embodiment the compound of Formula V is:

or a pharmaceutically acceptable salt thereof.

In one embodiment the compound of Formula V is:

or a pharmaceutically acceptable salt thereof.

In one embodiment the compound of Formula V is:

or a pharmaceutically acceptable salt thereof.

In one embodiment the compound of Formula V is:

or a pharmaceutically acceptable salt thereof.Embodiments of R¹

In one embodiment R¹ is fluoro.

In one embodiment R¹ is chloro.

In one embodiment R¹ is bromo.

In one embodiment R¹ is trifluoromethane.

In one embodiment R¹ is difluoromethane.

In one embodiment R¹ is monofluoromethane.

In one embodiment R¹ is methyl.

In one embodiment R¹ is ethyl.

In one embodiment R¹ is propyl.

In one embodiment R¹ is cyclopropyl.

In various independent embodiments there are 2, 3, 4, or 5, R¹s and atleast one R¹ is fluoro.

In various independent embodiments there are 2, 3, 4, or 5, R¹s and atleast one R¹ is chloro.

In various independent embodiments there are 2, 3, 4, or 5, R¹s and atleast one R¹ is bromo.

In various independent embodiments there are 2, 3, 4, or 5, R¹s and atleast one R¹ is trifluoromethane.

In various independent embodiments there are 2, 3, 4, or 5, R¹s and atleast one R¹ is methyl.

In various independent embodiments there are 2, 3, 4, or 5, R¹s and atleast one R¹ is ethyl.

In various independent embodiments there are 2, 3, 4, or 5, R¹s and atleast one R¹ is propyl.

In various independent embodiments there are 2, 3, 4, or 5, R¹s and atleast one R¹ is cyclopropyl.

In various independent embodiments there are 2, 3, 4, or 5, R¹s and atleast one R¹ is difluoromethane.

In various independent embodiments there are 2, 3, 4, or 5, R¹s and atleast one R¹ is monofluoromethane.

Embodiments of “Alkyl”

In one embodiment “alkyl” is a C₁-C₁₀alkyl, C₁-C₉alkyl, C₁-C₈alkyl,C₁-C₇alkyl, C₁-C₆alkyl, C₁-C₅alkyl, C₁-C₄alkyl, C₁-C₃alkyl, orC₁-C₂alkyl.

In one embodiment “alkyl” has one carbon.

In one embodiment “alkyl” has two carbons.

In one embodiment “alkyl” has three carbons.

In one embodiment “alkyl” has four carbons.

In one embodiment “alkyl” has five carbons.

In one embodiment “alkyl” has six carbons.

Non-limiting examples of“alkyl” include: methyl, ethyl, propyl, butyl,pentyl, and hexyl.

Additional non-limiting examples of “alkyl” include: isopropyl,isobutyl, isopentyl, and isohexyl.

Additional non-limiting examples of “alkyl” include: sec-butyl,sec-pentyl, and sec-hexyl.

Additional non-limiting examples of “alkyl” include: tert-butyl,tert-pentyl, and tert-hexyl.

Additional non-limiting examples of “alkyl” include: neopentyl,3-pentyl, and active pentyl.

Embodiments of “Haloalkyl”

In one embodiment “haloalkyl” is a C₁-C₁₀haloalkyl, C₁-C₉haloalkyl,C₁-C₈haloalkyl, C₁-C₇haloalkyl, C₁-C₆haloalkyl, C₁-C₅haloalkyl,C₁-C₄haloalkyl, C₁-C₃haloalkyl, and C₁-C₂haloalkyl.

In one embodiment “haloalkyl” has one carbon.

In one embodiment “haloalkyl” has one carbon and one halogen.

In one embodiment “haloalkyl” has one carbon and two halogens.

In one embodiment “haloalkyl” has one carbon and three halogens.

In one embodiment “haloalkyl” has two carbons.

In one embodiment “haloalkyl” has three carbons.

In one embodiment “haloalkyl” has four carbons.

In one embodiment “haloalkyl” has five carbons.

In one embodiment “haloalkyl” has six carbons.

Non-limiting examples of“haloalkyl” include:

Additional non-limiting examples of “haloalkyl” include:

Additional non-limiting examples of “haloalkyl” include:

Additional non-limiting examples of“haloalkyl” include:

Embodiments of “Aryl”

In one embodiment “aryl” is a 6 carbon aromatic group (phenyl)

In one embodiment “aryl” is a 10 carbon aromatic group (napthyl)

In one embodiment “aryl” is a 6 carbon aromatic group fused to aheterocycle wherein the point of attachment is the aryl ring.Non-limiting examples of “aryl” include indoline, tetrahydroquinoline,tetrahydroisoquinoline, and dihydrobenzofuran wherein the point ofattachment for each group is on the aromatic ring.

For example

is an “aryl” group.

However,

is a “heterocycle” group.

In one embodiment “aryl” is a 6 carbon aromatic group fused to acycloalkyl wherein the point of attachment is the aryl ring.Non-limiting examples of “aryl” include dihydro-indene andtetrahydronaphthalene wherein the point of attachment for each group ison the aromatic ring.

For example

is an “aryl” group.

However,

is a “cycloalkyl” group.Embodiments of “Heteroaryl”

In one embodiment “heteroaryl” is a 5 membered aromatic group containing1, 2, 3, or 4 nitrogen atoms.

Non-limiting examples of 5 membered “heteroaryl” groups include pyrrole,furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole,oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole,and thiatriazole.

Additional non-limiting examples of 5 membered “heteroaryl” groupsinclude:

In one embodiment “heteroaryl” is a 6 membered aromatic group containing1, 2, or 3 nitrogen atoms (i.e. pyridinyl, pyridazinyl, triazinyl,pyrimidinyl, and pyrazinyl).

Non-limiting examples of 6 membered “heteroaryl” groups with 1 or 2nitrogen atoms include:

In one embodiment “heteroaryl” is a 9 membered bicyclic aromatic groupcontaining 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

Non-limiting examples of “heteroaryl” groups that are bicyclic includeindole, benzofuran, isoindole, indazole, benzimidazole, azaindole,azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole,benzoisothiazole, benzooxazole, and benzothiazole.

Additional non-limiting examples of“heteroaryl” groups that are bicyclicinclude:

Additional non-limiting examples of “heteroaryl” groups that arebicyclic include:

Additional non-limiting examples of “heteroaryl” groups that arebicyclic include:

In one embodiment “heteroaryl” is a 10 membered bicyclic aromatic groupcontaining 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

Non-limiting examples of “heteroaryl” groups that are bicyclic includequinoline, isoquinoline, quinoxaline, phthalazine, quinazoline,cinnoline, and naphthyridine.

Additional non-limiting examples of “heteroaryl” groups that arebicyclic include:

Embodiments of “Cycloalkyl”

In one embodiment “cycloalkyl” is a C₃-C₈cycloalkyl, C₃-C₇cycloalkyl,C₃-C₆cycloalkyl, C₃-C₅cycloalkyl, C₃-C₄cycloalkyl, C₄-C₈cycloalkyl,C₅-C₈cycloalkyl, or C₆-C₈cycloalkyl.

In one embodiment “cycloalkyl” has three carbons.

In one embodiment “cycloalkyl” has four carbons.

In one embodiment “cycloalkyl” has five carbons.

In one embodiment “cycloalkyl” has six carbons.

In one embodiment “cycloalkyl” has seven carbons.

In one embodiment “cycloalkyl” has eight carbons.

In one embodiment “cycloalkyl” has nine carbons.

In one embodiment “cycloalkyl” has ten carbons.

Non-limiting examples of “cycloalkyl” include: cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

Additional non-limiting examples of “cycloalkyl” include dihydro-indeneand tetrahydronaphthalene wherein the point of attachment for each groupis on the cycloalkyl ring.

For example

is an “cycloalkyl” group.

However,

is an “aryl” group.Embodiments of “Heterocycle”

In one embodiment “heterocycle” refers to a cyclic ring with onenitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocycle” refers to a cyclic ring with onenitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocycle” refers to a cyclic ring with twonitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocycle” refers to a cyclic ring with one oxygenand 3, 4, 5, 6, 7, or 8 carbon atoms.

In one embodiment “heterocycle” refers to a cyclic ring with one sulfurand 3, 4, 5, 6, 7, or 8 carbon atoms.

Non-limiting examples of“heterocycle” include aziridine, oxirane,thiirane, azetidine, 1,3-diazetidine, oxetane, and thietane.

Additional non-limiting examples of “heterocycle” include pyrrolidine,3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

Additional non-limiting examples of“heterocycle” includetetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane,and 1,3-oxathiolane.

Additional non-limiting examples of “heterocycle” include piperidine,piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane,1,4-dithiane, morpholine, and thiomorpholine.

Additional non-limiting examples of “heterocycle” include indoline,tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuranwherein the point of attachment for each group is on the heterocyclicring.

For example,

is a “heterocycle” group.

However,

is an “aryl” group.Embodiments of “Arylalkyl”

In one embodiment the “arylalkyl” refers to a 1 carbon alkyl groupsubstituted with an aryl group.

Non-limiting examples of “arylalkyl” include:

In one embodiment “arylalkyl” is

In one embodiment the “arylalkyl” refers to a 2 carbon alkyl groupsubstituted with an aryl group.

Non-limiting examples of “arylalkyl” include:

In one embodiment the “arylalkyl” refers to a 3 carbon alkyl groupsubstituted with an aryl group.

Embodiments of R²

In one embodiment R² is 4-6 membered heterocycle optionally substitutedwith one, two, or three groups selected from R⁴.

In one embodiment R² is —NH₂.

In one embodiment R² is —NHalkyl.

In one embodiment R² is —NHCH₃.

In one embodiment R² is —NHCH₂CH₃.

In one embodiment R² is —N(alkyl)₂.

In one embodiment R² is —N(CH₃)₂.

In one embodiment R² is —N(CH₂CH₃)₂.

In one embodiment, R² is —OH.

In one embodiment R² is

In one embodiment R₂ is

In one embodiment R² is

In one embodiment R² is

In one embodiment R² is

In one embodiment R² is

In one embodiment R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

In various independent embodiments R² is

Embodiments of A

In one embodiment, A is selected from:

In another embodiment, A is selected from:

In another embodiment, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In various independent embodiments, A is selected from:

In an alternative embodiment, A is selected from:

wherein m3 is 1, 2, 3, or 4.Embodiments of X

In one embodiment, X is selected from:

In another embodiment, X is selected from:

In another embodiment, X is selected from:

In various independent embodiments, X is selected from:

In various independent embodiments, X is selected from:

In various independent embodiments, X is selected from:

In various independent embodiments, X is selected from:

In various independent embodiments, X is selected from:

In various independent embodiments, X is selected from:

In various independent embodiments, X is selected from:

In various independent embodiments, X is selected from:

In various independent embodiments, X is selected from:

In various independent embodiments, X is selected from:

In various independent embodiments, X is selected from:

In various independent embodiments, X is selected from:

In various independent embodiments, X is selected from:

In various independent embodiments, X is selected from:

In various independent embodiments, X is selected from:

In various independent embodiments, X is selected from:

In an alternative embodiment, X is selected from:

wherein m3 is 1, 2, 3, or 4.

In an alternative embodiment, Y is selected from:

wherein m3 is 1, 2, 3, or 4.

Embodiments of R¹²

In one embodiment R¹² is selected from:

In one embodiment R¹² is

In one embodiment R¹² is

In one embodiment R¹² is

In one embodiment R¹² is

Non-limiting examples of compounds of Formula I include:

Non-limiting examples of compounds of Formula I include:

Non-limiting examples of compounds of Formula I include:

Non-limiting examples of compounds of Formula I include:

Non-limiting examples of compounds of Formula I include:

Non-limiting examples of compounds of Formula I include:

Non-limiting examples of compounds of Formula I include:

Additional non-limiting examples of compounds of Formula I include:

Non-limiting examples of compounds of Formula I include:

Non-limiting examples of compounds of Formula I include:

Non-limiting examples of compounds of Formula II include:

Non-limiting examples of compounds of Formula II include:

Non-limiting examples of compounds of Formula II include:

Non-limiting examples of compounds of Formula II include:

Non-limiting examples of compounds of Formula II include:

Non-limiting examples of compounds of Formula II include:

Non-limiting examples of compounds of Formula II include:

Non-limiting examples of compounds of Formula II include:

Non-limiting examples of compounds of Formula II include:

Non-limiting examples of compounds of Formula II include:

Non-limiting examples of compounds of Formula III include:

Non-limiting examples of compounds of Formula III include:

Non-limiting examples of compounds of Formula III include:

Pharmaceutical Compositions and Dosage Forms

In some aspects, this invention is a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of FormulaI, II, III, or IV as described herein, and one or more pharmaceuticallyacceptable diluents, preservatives, solubilizers, emulsifiers,adjuvants, excipients, or carriers. Such excipients include liquids suchas water, saline, glycerol, polyethylene glycol, hyaluronic acid,ethanol, and the like.

The term “pharmaceutically acceptable carrier” refers to a diluent,adjuvant, excipient or carrier with which a compound of the disclosureis administered. The terms “effective amount” or “pharmaceuticallyeffective amount” refer to a nontoxic but sufficient amount of the agentto provide the desired biological result. That result can be reductionand/or alleviation of the signs, symptoms, or causes of a disease, orany other desired alteration of a biological system. An appropriate“effective” amount in any individual case can be determined by one ofordinary skill in the art using routine experimentation.“Pharmaceutically acceptable carriers” for therapeutic use are wellknown in the pharmaceutical art, and are described, for example, inRemington's Pharmaceutical Sciences, 18th Edition (Easton, Pa.: MackPublishing Company, 1990). For example, sterile saline andphosphate-buffered saline at physiological pH can be used.Preservatives, stabilizers, dyes and even flavoring agents can beprovided in the pharmaceutical composition. For example, sodiumbenzoate, sorbic acid and esters of p-hydroxybenzoic acid can be addedas preservatives. Id. at 1449. In addition, antioxidants and suspendingagents can be used. Id.

Suitable excipients for non-liquid formulations are also known to thoseof skill in the art. A thorough discussion of pharmaceuticallyacceptable excipients and salts is available in Remington'sPharmaceutical Sciences, 18th Edition (Easton, Pa.: Mack PublishingCompany, 1990).

Additionally, auxiliary substances, such as wetting or emulsifyingagents, biological buffering substances, surfactants, and the like, canbe present in such vehicles. A biological buffer can be any solutionwhich is pharmacologically acceptable and which provides the formulationwith the desired pH, i.e., a pH in the physiologically acceptable range.Examples of buffer solutions include saline, phosphate buffered saline,Tris buffered saline, Hank's buffered saline, and the like.

Depending on the intended mode of administration, the pharmaceuticalcompositions can be in the form of solid, semi-solid or liquid dosageforms, such as, for example, tablets, suppositories, pills, capsules,powders, liquids, suspensions, creams, ointments, lotions or the like,preferably in unit dosage form suitable for single administration of aprecise dosage. The compositions will include an effective amount of theselected drug in combination with a pharmaceutically acceptable carrierand, in addition, can include other pharmaceutical agents, adjuvants,diluents, buffers, and the like.

In general, the compositions of the disclosure will be administered in atherapeutically effective amount by any of the accepted modes ofadministration. Suitable dosage ranges depend upon numerous factors suchas the severity of the disease to be treated, the age and relativehealth of the subject, the potency of the compound used, the route andform of administration, the indication towards which the administrationis directed, and the preferences and experience of the medicalpractitioner involved. One of ordinary skill in the art of treating suchdiseases will be able, without undue experimentation and in relianceupon personal knowledge and the disclosure of this application, toascertain a therapeutically effective amount of the compositions of thedisclosure for a given disease.

Thus, the compositions of the disclosure can be administered aspharmaceutical formulations including those suitable for oral (includingbuccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal orparenteral (including intramuscular, intra-arterial, intrathecal,subcutaneous and intravenous) administration or in a form suitable foradministration by inhalation or insufflation. The preferred manner ofadministration is intravenous or oral using a convenient daily dosageregimen which can be adjusted according to the degree of affliction.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. Liquid pharmaceutically administrablecompositions can, for example, be prepared by dissolving, dispersing,and the like, an active compound as described herein and optionalpharmaceutical adjuvants in an excipient, such as, for example, water,saline, aqueous dextrose, glycerol, ethanol, and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered can also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like, for example, sodium acetate, sorbitanmonolaurate, triethanolamine sodium acetate, triethanolamine oleate, andthe like. Actual methods of preparing such dosage forms are known, orwill be apparent, to those skilled in this art; for example, seeRemington's Pharmaceutical Sciences, referenced above.

In yet another embodiment is the use of permeation enhancer excipientsincluding polymers such as: polycations (chitosan and its quaternaryammonium derivatives, poly-L-arginine, aminated gelatin); polyanions(N-carboxymethyl chitosan, poly-acrylic acid); and, thiolated polymers(carboxymethyl cellulose-cysteine, polycarbophil-cysteine,chitosan-thiobutylamidine, chitosan-thioglycolic acid,chitosan-glutathione conjugates).

For oral administration, the composition will generally take the form ofa tablet, capsule, a softgel capsule or can be an aqueous or nonaqueoussolution, suspension or syrup. Tablets and capsules are preferred oraladministration forms. Tablets and capsules for oral use can include oneor more commonly used carriers such as lactose and corn starch.Lubricating agents, such as magnesium stearate, are also typicallyadded. Typically, the compositions of the disclosure can be combinedwith an oral, non-toxic, pharmaceutically acceptable, inert carrier suchas lactose, starch, sucrose, glucose, methyl cellulose, magnesiumstearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol andthe like. Moreover, when desired or necessary, suitable binders,lubricants, disintegrating agents, and coloring agents can also beincorporated into the mixture. Suitable binders include starch, gelatin,natural sugars such as glucose or beta-lactose, corn sweeteners, naturaland synthetic gums such as acacia, tragacanth, or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride, and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

When liquid suspensions are used, the active agent can be combined withany oral, non-toxic, pharmaceutically acceptable inert carrier such asethanol, glycerol, water, and the like and with emulsifying andsuspending agents. If desired, flavoring, coloring and/or sweeteningagents can be added as well. Other optional components for incorporationinto an oral formulation herein include, but are not limited to,preservatives, suspending agents, thickening agents, and the like.

Parenteral formulations can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solubilizationor suspension in liquid prior to injection, or as emulsions. Preferably,sterile injectable suspensions are formulated according to techniquesknown in the art using suitable carriers, dispersing or wetting agentsand suspending agents. The sterile injectable formulation can also be asterile injectable solution or a suspension in a acceptably nontoxicparenterally acceptable diluent or solvent. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oils,fatty esters or polyols are conventionally employed as solvents orsuspending media. In addition, parenteral administration can involve theuse of a slow release or sustained release system such that a constantlevel of dosage is maintained.

Parenteral administration includes intraarticular, intravenous,intramuscular, intradermal, intraperitoneal, and subcutaneous routes,and include aqueous and non-aqueous, isotonic sterile injectionsolutions, which can contain antioxidants, buffers, bacteriostats, andsolutes that render the formulation isotonic with the blood of theintended recipient, and aqueous and non-aqueous sterile suspensions thatcan include suspending agents, solubilizers, thickening agents,stabilizers, and preservatives. Administration via certain parenteralroutes can involve introducing the formulations of the disclosure intothe body of a patient through a needle or a catheter, propelled by asterile syringe or some other mechanical device such as an continuousinfusion system. A formulation provided by the disclosure can beadministered using a syringe, injector, pump, or any other devicerecognized in the art for parenteral administration.

Preferably, sterile injectable suspensions are formulated according totechniques known in the art using suitable carriers, dispersing orwetting agents and suspending agents. The sterile injectable formulationcan also be a sterile injectable solution or a suspension in a nontoxicparenterally acceptable diluent or solvent. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oils,fatty esters or polyols are conventionally employed as solvents orsuspending media. In addition, parenteral administration can involve theuse of a slow release or sustained release system such that a constantlevel of dosage is maintained.

Preparations according to the disclosure for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, oremulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil and cornoil, gelatin, and injectable organic esters such as ethyl oleate. Suchdosage forms can also contain adjuvants such as preserving, wetting,emulsifying, and dispersing agents. They can be sterilized by, forexample, filtration through a bacteria retaining filter, byincorporating sterilizing agents into the compositions, by irradiatingthe compositions, or by heating the compositions. They can also bemanufactured using sterile water, or some other sterile injectablemedium, immediately before use.

Sterile injectable solutions are prepared by incorporating one or moreof the compounds of the disclosure in the required amount in theappropriate solvent with various of the other ingredients enumeratedabove, as required, followed by filtered sterilization. Generally,dispersions are prepared by incorporating the various sterilized activeingredients into a sterile vehicle which contains the basic dispersionmedium and the required other ingredients from those enumerated above.In the case of sterile powders for the preparation of sterile injectablesolutions, the preferred methods of preparation are vacuum-drying andfreeze-drying techniques which yield a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof. Thus, for example, a parenteralcomposition suitable for administration by injection is prepared bystirring 1.50% by weight of active ingredient in 10% by volume propyleneglycol and water. The solution is made isotonic with sodium chloride andsterilized.

Alternatively, the pharmaceutical compositions of the disclosure can beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable nonirritatingexcipient which is solid at room temperature but liquid at the rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of the disclosure can also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and can be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, propellants such as fluorocarbons or nitrogen, and/orother conventional solubilizing or dispersing agents.

Preferred formulations for topical drug delivery are ointments andcreams. Ointments are semisolid preparations which are typically basedon petrolatum or other petroleum derivatives. Creams containing theselected active agent, are, as known in the art, viscous liquid orsemisolid emulsions, either oil-in-water or water-in-oil. Cream basesare water-washable, and contain an oil phase, an emulsifier and anaqueous phase. The oil phase, also sometimes called the “internal”phase, is generally comprised of petrolatum and a fatty alcohol such ascetyl or stearyl alcohol. The aqueous phase usually, although notnecessarily, exceeds the oil phase in volume, and generally contains ahumectant. The emulsifier in a cream formulation is generally anonionic, anionic, cationic or amphoteric surfactant. The specificointment or cream base to be used, as will be appreciated by thoseskilled in the art, is one that will provide for optimum drug delivery.As with other carriers or vehicles, an ointment base should be inert,stable, nonirritating and nonsensitizing.

Formulations for buccal administration include tablets, lozenges, gelsand the like. Alternatively, buccal administration can be effected usinga transmucosal delivery system as known to those skilled in the art. Thecompounds of the disclosure can also be delivered through the skin ormucosal tissue using conventional transdermal drug delivery systems,i.e., transdermal “patches” wherein the agent is typically containedwithin a laminated structure that serves as a drug delivery device to beaffixed to the body surface. In such a structure, the drug compositionis typically contained in a layer, or “reservoir,” underlying an upperbacking layer. The laminated device can contain a single reservoir, orit can contain multiple reservoirs. In one embodiment, the reservoircomprises a polymeric matrix of a pharmaceutically acceptable contactadhesive material that serves to affix the system to the skin duringdrug delivery. Examples of suitable skin contact adhesive materialsinclude, but are not limited to, polyethylenes, polysiloxanes,polyisobutylenes, polyacrylates, polyurethanes, and the like.Alternatively, the drug-containing reservoir and skin contact adhesiveare present as separate and distinct layers, with the adhesiveunderlying the reservoir which, in this case, can be either a polymericmatrix as described above, or it can be a liquid or gel reservoir, orcan take some other form. The backing layer in these laminates, whichserves as the upper surface of the device, functions as the primarystructural element of the laminated structure and provides the devicewith much of its flexibility. The material selected for the backinglayer should be substantially impermeable to the active agent and anyother materials that are present.

The compositions of the disclosure can be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound may, for example generally havea small particle size for example of the order of 5 microns or less.Such a particle size can be obtained by means known in the art, forexample by micronization. The active ingredient is provided in apressurized pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide or other suitable gas. Theaerosol can conveniently also contain a surfactant such as lecithin. Thedose of drug can be controlled by a metered valve. Alternatively theactive ingredients can be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition can be presented in unitdose form for example in capsules or cartridges of e.g., gelatin orblister packs from which the powder can be administered by means of aninhaler.

A pharmaceutically or therapeutically effective amount of thecomposition will be delivered to the subject. The precise effectiveamount will vary from subject to subject and will depend upon thespecies, age, the subject's size and health, the nature and extent ofthe condition being treated, recommendations of the treating physician,and the therapeutics or combination of therapeutics selected foradministration, the effective amount for a given situation can bedetermined by routine experimentation. For purposes of the disclosure, atherapeutic amount may for example be in the range of about 0.01 mg/kgto about 250 mg/kg body weight, more preferably about 0.1 mg/kg to about10 mg/kg, in at least one dose. In larger mammals the indicated dailydosage can be from about 1 mg to 300 mg, one or more times per day, morepreferably in the range of about 10 mg to 200 mg. The subject can beadministered as many doses as is required to reduce and/or alleviate thesigns, symptoms, or causes of the disorder in question, or bring aboutany other desired alteration of a biological system. When desired,formulations can be prepared with enteric coatings adapted for sustainedor controlled release administration of the active ingredient.

The therapeutically effective dosage of any active compound describedherein will be determined by the health care practitioner depending onthe condition, size and age of the patient as well as the route ofdelivery. In one non-limited embodiment, a dosage from about 0.1 toabout 200 mg/kg has therapeutic efficacy, with all weights beingcalculated based upon the weight of the active compound, including thecases where a salt is employed. In some embodiments, the dosage may bethe amount of compound needed to provide a serum concentration of theactive compound of up to about 10 nM, 50 nM, 100 nM, 200 nM, 300 nM, 400nM, 500 nM, 600 nM, 700 nM, 800 nM, 900 nM, 1 μM, 5 μM, 10 μM, 20 μM, 30μM, or 40 μM.

In certain embodiments the pharmaceutical composition is in a dosageform that contains from about 0.1 mg to about 2000 mg, from about 10 mgto about 1000 mg, from about 100 mg to about 800 mg, or from about 200mg to about 600 mg of the active compound and optionally from about 0.1mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100mg to about 800 mg, or from about 200 mg to about 600 mg of anadditional active agent in a unit dosage form. Examples of dosage formswith at least 5, 10, 15, 20, 25, 50, 100, 200, 250, 300, 400, 500, 600,700, 750, 800, 850, 900, 950 or 1000 mg of active compound, or its salt.The pharmaceutical composition may also include a molar ratio of theactive compound and an additional active agent, in a ratio that achievesthe desired results.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Methods of Treatment

The compounds and compositions of the invention may be used in methodsfor treatment or prevention of estrogen-related medical disorders, forexample, cancer. The cancer may be a breast cancer, a uterine cancer, anovarian cancer, a prostate cancer, and a lung cancer. Particularly, thebreast cancer may be a tamoxifen resistant breast cancer or a triplenegative breast cancer.

In one embodiment “cancer” refers to an abnormal growth of cells whichtend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread). The types of cancer include, but is not limitedto, solid tumors (such as those of the bladder, bowel, brain, breast,endometrium, heart, kidney, lung, uterus, lymphatic tissue (lymphoma),ovary, pancreas or other endocrine organ (thyroid), prostate, skin(melanoma or basal cell cancer) or hematological tumors (such as theleukemias and lymphomas) at any stage of the disease with or withoutmetastases.

In one embodiment, the cancer or tumor is estrogen-mediated. In analternative embodiment, the cancer or tumor is not estrogen-mediated. Invariable embodiments, the cancer or tumor is not hormone-mediated.Non-limiting examples of cancers include, acute lymphoblastic leukemia,acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendixcancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cellcarcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcomaand malignant fibrous histiocytoma), brain stem glioma, brain tumors,brain and spinal cord tumors, breast cancer, bronchial tumors, Burkittlymphoma, cervical cancer, chronic lymphocytic leukemia, chronicmyelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cutaneous T-Cell lymphoma, embryonal tumors,endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer,ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladdercancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumor (GIST), gastrointestinal stromal celltumor, germ cell tumor, glioma, hairy cell leukemia, head and neckcancer, hepatocellular (liver) cancer, hodgkin lymphoma, hypopharyngealcancer, intraocular melanoma, islet cell tumors (endocrine pancreas),Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngealcancer, leukemia, Acute lymphoblastic leukemia, acute myeloid leukemia,chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cellleukemia, liver cancer, lung cancer, non-small cell lung cancer, smallcell lung cancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkinlymphoma, non-Hodgkin lymphoma, lymphoma, Waldenström macroglobulinemia,medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouthcancer, chronic myelogenous leukemia, myeloid leukemia, multiplemyeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma,non-small cell lung cancer, oral cancer, oropharyngeal cancer,osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer,ovarian epithelial cancer, ovarian germ cell tumor, ovarian lowmalignant potential tumor, pancreatic cancer, papillomatosis,parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymaltumors of intermediate differentiation, pineoblastoma and supratentorialprimitive neuroectodermal tumors, pituitary tumor, plasma cellneoplasm/multiple myeloma, pleuropulmonary blastoma, primary centralnervous system lymphoma, prostate cancer, rectal cancer, renal cell(kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary glandcancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, kaposi, Sézarysyndrome, skin cancer, small cell Lung cancer, small intestine cancer,soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer,supratentorial primitive neuroectodermal tumors, T-cell lymphoma,testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroidcancer, urethral cancer, uterine cancer, uterine sarcoma, vaginalcancer, vulvar cancer, Waldenström macroglobulinemia, Wilms tumor.

The method of treatment may prevent or reduce the risk of cancer. Themethod of treatment may cause partial or complete regression of cancerin a subject.

The method of treatment may cause partial or complete regression of atamoxifen resistant cancer or tumor. The method of treatment may causepartial or complete regression of a triple negative breast cancer.

In some embodiments, compounds disclosed herein are used to treat orprevent cancer or a tumor in a mammal, such as a human. In someembodiments, the cancer is breast cancer, ovarian cancer, endometrialcancer, prostate cancer, or uterine cancer. In some embodiments, thecancer is breast cancer, lung cancer, ovarian cancer, endometrialcancer, prostate cancer, or uterine cancer. In some embodiments, thecancer is breast cancer. In some embodiments, the cancer is a hormonedependent cancer. In some embodiments, the cancer is an estrogenreceptor dependent cancer. In some embodiments, the cancer is anestrogen-sensitive cancer. In some embodiments, the cancer is resistantto anti-hormonal treatment. In some embodiments, the cancer is anestrogen-sensitive cancer or an estrogen receptor dependent cancer thatis resistant to anti-hormonal treatment. In some embodiments, the canceris a hormone-sensitive cancer or a hormone receptor dependent cancerthat is resistant to anti-hormonal treatment. In some embodiments,anti-hormonal treatment includes treatment with at least one agentselected from tamoxifen, fulvestrant, steroidal aromatase inhibitors,and non-steroidal aromatase inhibitors.

In some embodiments, compounds disclosed herein are used to treathormone receptor positive metastatic breast cancer in a postmenopausalwoman with disease progression following anti-estrogen therapy.

In some embodiments, compounds disclosed herein are used to treat ahormonal dependent benign or malignant disease of the breast orreproductive tract in a mammal. In some embodiments, the benign ormalignant disease is breast cancer.

In one embodiment a compound of the present invention is used forhormone therapy.

The foregoing may be better understood by reference to the followingExamples, which are presented for purposes of illustration and are notintended to limit the scope of the invention.

In one aspect, a compound of the present invention or itspharmaceutically acceptable salt or prodrug, can be used to treat ahormone-related cancer or tumor that has metastasized to the brain, boneor other organ. In one embodiment of this aspect, the hormone-relatedcancer is estrogen mediated. In another embodiment, the estrogenmediated cancer is selected from breast, uterine, ovarian andendometrial. In other embodiments, a compound of the present inventionor its pharmaceutically acceptable salt or prodrug, can be used toprevent a hormone-related cancer or tumor from metastasizing to thebrain, bone or other organ, including a hormone-related cancer that isestrogen mediated, for example, breast, uterine, ovarian or endometrial.

Combination Therapy

In one aspect, a compound of Formula I, Formula II, Formula III, orFormula IV of the present invention is administered in combination witha compound of Formula V in a single fixed dosage form once, twice, orthree times a day, which may have the benefit of treatment compliance.In another embodiment, the drugs are formulated together into two ormore fixed dosage forms, which are taken simultaneously or over thecourse of the day, for example once, twice, or three times a day, asprescribed by a healthcare provider. In yet another embodiment, thedrugs are provided in separate pills and are administered approximatelysimultaneously or at varying times throughout the day. When the drugsare provided in separate dosage forms, in one embodiment they areadministered in a manner that an effective amount of both of the drugs(C_(trough)) is present simultaneously in the body.

In one aspect, a method for the treatment of a disorder of abnormalcellular proliferation in a host such as a human is provided thatincludes administering an effective amount of a combination of one ormore of the active compounds described herein in combination oralternation with another active compound.

In one aspect of this embodiment, the additional active compound is animmune modulator, including but not limited to a checkpoint inhibitor. Acheckpoint inhibitor for use in the methods described herein include,but are not limited to a PD-1 inhibitor, PD-L1 inhibitor, PD-L2inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, andV-domain Ig suppressor of T-cell activation (VISTA) inhibitor, orcombination thereof.

In one embodiment, the checkpoint inhibitor is a PD-1 inhibitor thatblocks the interaction of PD-1 and PD-L1 by binding to the PD-1receptor, and in turn inhibits immune suppression. In one embodiment,the checkpoint inhibitor is a PD-1 checkpoint inhibitor selected fromnivolumab, pembrolizumab, pidilizumab, AMP-224 (AstraZeneca andMedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001(Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui MedicineCompany and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1/VISTAinhibitor CA-170 (Curis Inc.).

In one embodiment, the checkpoint inhibitor is a PD-L1 inhibitor thatblocks the interaction of PD-1 and PD-L1 by binding to the PD-L1receptor, and in turn inhibits immune suppression. PD-L inhibitorsinclude, but are not limited to, avelumab, atezolizumab, durvalumab,KN035, and BMS-936559 (Bristol-Myers Squibb).

In one aspect of this embodiment, the checkpoint inhibitor is a CTLA-4checkpoint inhibitor that binds to CTLA-4 and inhibits immunesuppression. CTLA-4 inhibitors include, but are not limited to,ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884 andAGEN2041 (Agenus).

In another embodiment, the checkpoint inhibitor is a LAG-3 checkpointinhibitor. Examples of LAG-3 checkpoint inhibitors include, but are notlimited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781(GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and thedual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). In yet anotheraspect of this embodiment, the checkpoint inhibitor is a TIM-3checkpoint inhibitor. A specific TIM-3 inhibitor includes, but is notlimited to, TSR-022 (Tesaro).

In yet another embodiment, one of the active compounds described hereinis administered in an effective amount for the treatment of abnormaltissue of the female reproductive system such as breast, ovarian,kidney, endometrial, or uterine cancer, in combination or alternationwith an effective amount of an estrogen inhibitor including but notlimited to a SERM (selective estrogen receptor modulator), a SERD(selective estrogen receptor downregulator), a complete estrogenreceptor downregulator, or another form of partial or complete estrogenantagonist. Partial anti-estrogens like raloxifene and tamoxifen retainsome estrogen-like effects, including an estrogen-like stimulation ofuterine growth, and also, in some cases, an estrogen-like action duringbreast cancer progression which stimulates tumor growth. In contrast,fulvestrant, a complete anti-estrogen, is free of estrogen-like actionon the uterus and is effective in tamoxifen-resistant tumors.Non-limiting examples of anti-estrogen compounds are provided in WO2014/19176 assigned to AstraZeneca. Additional non-limiting examples ofanti-estrogen compounds include: SERMS such as anordrin, bazedoxifene,broparestriol, chlorotrianisene, clomiphene citrate, cyclofenil,lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, andfulvestrant; aromatase inhibitors such as aminoglutethimide,testolactone, anastrozole, exemestane, fadrozole, formestane, andletrozole; and antigonadotropins such as leuprorelin, cetrorelix,allylestrenol, chloromadinone acetate, cyproterone acetate, delmadinoneacetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate,nomegestrol acetate, norethisterone acetate, progesterone, andspironolactone.

In another embodiment, one of the active compounds described herein isadministered in an effective amount for the treatment of abnormal tissueof the male reproductive system such as prostate or testicular cancer,in combination or alternation with an effective amount of an androgen(such as testosterone) inhibitor including but not limited to aselective androgen receptor modulator, a selective androgen receptordownregulator and/or degrader, a complete androgen receptor degrader, oranother form of partial or complete androgen antagonist. In oneembodiment, the prostate or testicular cancer is androgen-resistant.Non-limiting examples of anti-androgen compounds are provided in WO2011/156518 and U.S. Pat. Nos. 8,455,534 and 8,299,112. Additionalnon-limiting examples of anti-androgen compounds include: enzalutamide,apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone,canrenone, drospirenone, ketoconazole, topilutamide, abirateroneacetate, and cimetidine.

In one aspect, a treatment regimen is provided comprising theadministration of a compound of the present invention in combinationwith at least one additional chemotherapeutic agent. The combinationsdisclosed herein can be administered for beneficial, additive, orsynergistic effect in the treatment of abnormal cellular proliferativedisorders.

In specific embodiments, the treatment regimen includes theadministration of a compound of the present invention in combinationwith at least one kinase inhibitor. In one embodiment, the at least onekinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K)inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, or a spleentyrosine kinase (Syk) inhibitor, or a combination thereof.

PI3k inhibitors that may be used in the present invention are wellknown. Examples of PI3 kinase inhibitors include but are not limited toWortmannin, demethoxyviridin, perifosine, idelalisib, pictilisib,Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib,GS-9820, GDC-0032(2-[4-[2-(2-Isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropanamide),MLN-1117 ((2R)-1-Phenoxy-2-butanyl hydrogen (S)-methylphosphonate; orMethyl(oxo) {[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium)), BYL-719((2S)—N1-[4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide),GSK2126458(2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide),TGX-221((±)-7-Methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidin-4-one),GSK2636771(2-Methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylicacid dihydrochloride), KIN-193((R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoicacid), TGR-1202/RP5264, GS-9820((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-mohydroxypropan-1-one),GS-1101(5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one),AMG-319, GSK-2269557, SAR245409(N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4methylbenzamide), BAY80-6946(2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinaz),AS 252424(5-[1-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione),CZ 24832(5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide),buparlisib(5-[2,6-Di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine),GDC-0941(2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine),GDC-0980((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)),SF1126((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecan-18-oate),PF-05212384 (N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N-[4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]urea),LY3023414, BEZ235(2-Methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile),XL-765(N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide),and GSK1059615(5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidenedione),PX886([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5h]isochromen-10-yl]acetate (also known as sonolisib)).

In one embodiment, the compound of the present invention is combined ina single dosage form with the PIk3 inhibitor.

BTK inhibitors for use in the present invention are well known. Examplesof BTK inhibitors include ibrutinib (also known asPCI-32765)(Imbruvica™)(1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one),dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291/292(N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide)(Avila Therapeutics) (see US Patent Publication No 2011/0117073,incorporated herein in its entirety), dasatinib([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide],LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-ibromophenyl)propenamide), GDC-0834([R?-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide],CGI-5604-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide,CGI-1746(4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide),CNX-774(4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide),CTA056(7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-H-imidazo[4,5-g]quinoxalin-6(5H)-one),GDC-0834((R)—N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide),GDC-0837((R)—N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide),HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607(4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamidehydrochloride), QL-47(1-(1-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyridin-2(1H)-one),and RN486(6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one),and other molecules capable of inhibiting BTK activity, for examplethose BTK inhibitors disclosed in Akinleye et ah, Journal of Hematology& Oncology, 2013, 6:59, the entirety of which is incorporated herein byreference. In one embodiment, the compound of the present invention iscombined in a single dosage form with the BTK inhibitor.

Syk inhibitors for use in the present invention are well known, andinclude, for example, Cerdulatinib(4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide),entospletinib(6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine),fostamatinib([6-({5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyldihydrogen phosphate), fostamatinib disodium salt (sodium(6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methylphosphate), BAY 61-3606(2-(7-(3,4-Dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamideHCl), RO9021(6-[(1R,2S)-2-Amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylicacid amide), imatinib (Gleevec;4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-([4-(pyridin-3-yl)pyrimidin-2-yl]aminophenyl)benzamide), staurosporine, GSK143(2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide),PP2(1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine),PRT-060318(2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide),PRT-062607(4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamidehydrochloride), R112(3,3′-((5-fluoropyrimidine-2,4-diyl)bis(azanediyl))diphenol), R348(3-Ethyl-4-methylpyridine), R406(6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one),YM193306 (see Singh et al. Discovery and Development of Spleen TyrosineKinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643),7-azaindole, piceatannol, ER-27319 (see Singh et al. Discovery andDevelopment of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem.2012, 55, 3614-3643 incorporated in its entirety herein), Compound D(see Singh et al. Discovery and Development of Spleen Tyrosine Kinase(SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), PRT060318 (see Singh et al. Discovery and Developmentof Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), luteolin (see Singh etal. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), apigenin (see Singh et al. Discovery and Developmentof Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), quercetin (see Singh etal. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), fisetin (see Singh et al. Discovery and Development ofSpleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein), myricetin (see Singh etal. Discovery and Development of Spleen Tyrosine Kinase (SYK)Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in itsentirety herein), morin (see Singh et al. Discovery and Development ofSpleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 incorporated in its entirety herein). In one embodiment, thecompound of the present invention is combined in a single dosage formwith the Syk inhibitor.

In one embodiment, the at least one additional chemotherapeutic agent isa B-cell lymphoma 2 (Bcl-2) protein inhibitor. BCL-2 inhibitors areknown in the art, and include, for example, ABT-199(4-[4-[[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide),ABT-737(4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide), ABT-263((R)-4-(4-((4′-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide),GX15-070 (obatoclax mesylate,(2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole;methanesulfonic acid))), 2-methoxy-antimycin A3, YC137(4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester),pogosin, ethyl2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate,Nilotinib-d3, TW-37(N-[4-[[2-(1,1-Dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide),Apogossypolone (ApoG2), or G3139 (Oblimersen). In one embodiment, thecompound of the present invention is combined in a single dosage formwith the at least one BCL-2 inhibitor.

The compound of the present invention or its pharmaceutically activesalt can be combined with an immunotherapy. As discussed in more detailbelow, the compound of the present invention can be conjugated to anantibody, radioactive agent, or other targeting agent that directs thecompound to the diseased or abnormally proliferating cell.

In one embodiment, the additional therapy is a monoclonal antibody(MAb). Some MAbs stimulate an immune response that destroys cancercells. Similar to the antibodies produced naturally by B cells, theseMAbs “coat” the cancer cell surface, triggering its destruction by theimmune system. For example, bevacizumab targets vascular endothelialgrowth factor (VEGF), a protein secreted by tumor cells and other cellsin the tumor's microenvironment that promotes the development of tumorblood vessels. When bound to bevacizumab, VEGF cannot interact with itscellular receptor, preventing the signaling that leads to the growth ofnew blood vessels. Similarly, cetuximab and panitumumab target theepidermal growth factor receptor (EGFR), and trastuzumab targets thehuman epidermal growth factor receptor 2 (HER-2). MAbs, which bind tocell surface growth factor receptors, prevent the targeted receptorsfrom sending their normal growth-promoting signals. They may alsotrigger apoptosis and activate the immune system to destroy tumor cells.

In some embodiments, the combination can be administered to the subjectin further combination with other chemotherapeutic agents. Ifconvenient, the combination described herein can be administered at thesame time as another chemotherapeutic agent in order to simplify thetreatment regimen. In some embodiments, the combination and the otherchemotherapeutic can be provided in a single formulation. In oneembodiment, the use of the compounds described herein is combined in atherapeutic regime with other agents. Such agents may include, but arenot limited to, tamoxifen, midazolam, letrozole, bortezomib,anastrozole, goserelin, an mTOR inhibitor, a PI3 kinase inhibitors, dualmTOR-PI3K inhibitors, MEK inhibitors, RAS inhibitors, ALK inhibitors,HSP inhibitors (for example, HSP70 and HSP 90 inhibitors, or acombination thereof), BCL-2 inhibitors, apoptotic compounds, AKTinhibitors, including but not limited to, MK-2206, GSK690693,Perifosine, (KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol,PF-04691502, and Miltefosine, PD-1 inhibitors including but not limitedto, Nivolumab, CT-011, MK-3475, BMS936558, and AMP-514 or FLT-3inhibitors, including but not limited to, P406, Dovitinib, Quizartinib(AC220), Amuvatinib (MP-470), Tandutinib (MLN518), ENMD-2076, andKW-2449, or combinations thereof. Examples of mTOR inhibitors includebut are not limited to rapamycin and its analogs, everolimus (Afinitor),temsirolimus, ridaforolimus (Deforolimus), and sirolimus. Examples ofMEK inhibitors include but are not limited to trametinib/GSK1120212(N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide),selumetinib(6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide),pimasertib/AS703026/MSC1935369 ((S)—N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide),XL-518/GDC-0973(1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol),refametinib/BAY869766/RDEA119(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide),PD-0325901(N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide),TAK733((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione),MEK162/ARRY438162(5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6carboxamide), R05126766(3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one),WX-554, R04987655/CH4987655(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2yl)methyl)benzamide), or AZD8330(2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide).Examples of RAS inhibitors include but are not limited to Reolysin andsiG12D LODER. Examples of ALK inhibitors include but are not limited toCrizotinib, AP26113, and LDK378. HSP inhibitors include but are notlimited to Geldanamycin or 17-N-Allylamino-17-demethoxygeldanamycin(17AAG), and Radicicol. In a particular embodiment, a compound describedherein is administered in combination with letrozole and/or tamoxifen.Other chemotherapeutic agents that can be used in combination with thecompounds described herein include, but are not limited to,chemotherapeutic agents that do not require cell cycle activity fortheir anti-neoplastic effect.

In one embodiment, a compound of the present invention described hereincan be combined with a chemotherapeutic selected from, but are notlimited to, Imatinib mesylate (Gleevec®), Dasatinib (Sprycel®),Nilotinib (Tasigna®), Bosutinib (Bosulift), Trastuzumab (Herceptin®),Pertuzumab (Perjeta™), Lapatinib (Tykerb®), Gefitinib (Iressa®),Erlotinib (Tarceva®), Cetuximab (Erbitux®), Panitumumab (Vectibix®),Vandetanib (Caprelsa®), Vemurafenib (Zelboraf®), Vorinostat (Zolinza®),Romidepsin (Istodax®), Bexarotene (Targretin®), Alitretinoin(Panretin®), Tretinoin (Vesanoid®), Carfilzomib (Kyprolis™),Pralatrexate (Folotyn®), Bevacizumab (Avastin®), Ziv-aflibercept(Zaltrap®), Sorafenib (Nexavar®), Sunitinib (Sutent®), Pazopanib(Votrient®), Regorafenib (Stivarga®), and Cabozantinib (Cometriq™).

In certain aspects, the additional therapeutic agent is ananti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic,additional therapeutic agents, or immunosuppressive agents.

Suitable chemotherapeutic agents include, but are not limited to,radioactive molecules, toxins, also referred to as cytotoxins orcytotoxic agents, which includes any agent that is detrimental to theviability of cells, agents, and liposomes or other vesicles containingchemotherapeutic compounds. General anticancer pharmaceutical agentsinclude: Vincristine (Oncovin®) or liposomal vincristine (Marqibo®),Daunorubicin (daunomycin or Cerubidine®) or doxorubicin (Adriamycin®),Cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L-asparaginase(Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide(VP-16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®),Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, Dexamethasone(Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib(Tasigna®), bosutinib (Bosulif®), and ponatinib (Iclusig™). Examples ofadditional suitable chemotherapeutic agents include but are not limitedto 1-dehydrotestosterone, 5-fluorouracil, dacarbazine, 6-mercaptopurine,6-thioguanine, actinomycin D, adriamycin, alkylating agents, allopurinolsodium, altretamine, amifostine, anastrozole, anthramycin (AMC)),anti-mitotic agents, cis-dichlorodiamine platinum (II) (DDP) cisplatin),diamino dichloro platinum, anthracyclines, antibiotics, antimetabolites,asparaginase, BCG live (intravesical), betamethasone sodium phosphateand betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan,calcium leucovorin, calicheamicin, capecitabine, carboplatin, lomustine(CCNU), carmustine (BSNU), Chlorambucil, Cisplatin, Cladribine,Colchicine, conjugated estrogens, Cyclophosphamide, Cyclothosphamide,Cytarabine, Cytarabine, cytochalasin B, Cytoxan, Dacarbazine,Dactinomycin, dactinomycin (formerly actinomycin), daunorubicin HCl,daunorubicin citrate, denileukin diftitox, Dexrazoxane, Dibromomannitol,dihydroxy anthracin dione, Docetaxel, dolasetron mesylate, doxorubicinHCl, dronabinol, E. coli L-asparaginase, emetine, epoetin-α, ErwiniaL-asparaginase, esterified estrogens, estradiol, estramustine phosphatesodium, ethidium bromide, ethinyl estradiol, etidronate, etoposidecitrovorum factor, etoposide phosphate, filgrastim, floxuridine,fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinicacid, gemcitabine HCl, glucocorticoids, goserelin acetate, gramicidin D,granisetron HCl, hydroxyurea, idarubicin HCl, ifosfamide, interferonα-2b, irinotecan HCl, letrozole, leucovorin calcium, leuprolide acetate,levamisole HCl, lidocaine, lomustine, maytansinoid, mechlorethamine HCl,medroxyprogesterone acetate, megestrol acetate, melphalan HCl,mercaptopurine, Mesna, methotrexate, methyltestosterone, mithramycin,mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate,ondansetron HCl, paclitaxel, pamidronate disodium, pentostatin,pilocarpine HCl, plicamycin, polifeprosan 20 with carmustine implant,porfimer sodium, procaine, procarbazine HCl, propranolol, sargramostim,streptozotocin, tamoxifen, taxol, teniposide, teniposide, testolactone,tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan HCl,toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastinesulfate, vincristine sulfate, and vinorelbine tartrate.

Additional therapeutic agents that can be administered in combinationwith a compound disclosed herein can include 2-methoxyestradiol or 2ME2,finasunate, vatalanib, volociximab, etaracizumab (MEDI-522),cilengitide, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab,aldesleukin, atlizumab, tocilizumab, lucatumumab, dacetuzumab, HLL1,huN901-DM1, atiprimod, natalizumab, bortezomib, marizomib, tanespimycin,saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate,belinostat, panobinostat, mapatumumab, lexatumumab, dulanermin,plitidepsin, talmapimod, P276-00, enzastaurin, tipifarnib, lenalidomide,thalidomide, pomalidomide, simvastatin, and celecoxib.

In one aspect of the present invention, a compound described herein canbe combined with at least one immunosuppressive agent. Theimmunosuppressive agent in one embodiment is selected from the groupconsisting of a calcineurin inhibitor, e.g. a cyclosporin or anascomycin, e.g. Cyclosporin A (Neoral®), FK506 (tacrolimus),pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof,e.g. Sirolimus (Rapamune®), Everolimus (Certican®), temsirolimus,zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g. ridaforolimus,azathioprine, campath 1H, a SIP receptor modulator, e.g. fingolimod oran analogue thereof, an anti IL-8 antibody, mycophenolic acid or a saltthereof, e.g. sodium salt, or a prodrug thereof, e.g. MycophenolateMofetil (CellCept®), OKT3 (Orthoclone OKT3®), Prednisone, ATGAM®,Thymoglobulin®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1,15-deoxyspergualin, tresperimus, Leflunomide Arava®, anti-CD25,anti-IL2R, Basiliximab (Simulect®), Daclizumab (Zenapax®), mizoribine,methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus,Elidel®), CTLA41g, Abatacept, belatacept, LFA31g, etanercept (sold asEnbrel® by ImmuneXcite), adalimumab (Humira®), infliximab (Remicade®),an anti-LFA-1 antibody, natalizumab (Antegren®), Enlimomab, gavilimomab,Golimumab, antithymocyte immunoglobulin, siplizumab, Alefacept,efalizumab, Pentasa, mesalazine, asacol, codeine phosphate, benorylate,fenbufen, naprosyn, diclofenac, etodolac, indomethacin, aspirin, andibuprofen.

In certain embodiments, a compound described herein is administered tothe subject prior to treatment with another chemotherapeutic agent,during treatment with another chemotherapeutic agent, afteradministration of another chemotherapeutic agent, or a combinationthereof.

Synthetic Methods

The compounds described herein can be prepared by methods known by thoseskilled in the art. In one non-limiting example the disclosed compoundscan be prepared using the schemes.

Some of the compounds described herein can have a chiral center, and thecompound can exist in isomeric or diastereomeric form. When multiplechiral variables are present on formulas of the present invention, theformula further encompasses every possible diastereomer unless indicatedotherwise or clear from the text. For example (R,R), (S,R), (S,S), and(R,S) for a molecule with two chiral centers. One skilled in the artwill recognize that pure enantiomers, diastereomers, and cis/transisomers can be prepared by methods known in the art. Examples of methodsto obtain optically active materials include at least the following.

i) Physical separation of crystals—a technique whereby macroscopiccrystals of the individual enantiomers are manually separated. Thistechnique can be used if crystals of the separate enantiomers exist,i.e., the material is a conglomerate, and the crystals are visuallydistinct;

ii) Simultaneous crystallization—a technique whereby the individualenantiomers are separately crystallized from a solution of the racemate,possible only if the latter is a conglomerate in the solid state;

iii) Enzymatic resolutions—a technique whereby partial or completeseparation of a racemate by virtue of differing rates of reaction forthe enantiomers with an enzyme;

iv) Enzymatic asymmetric synthesis—a synthetic technique whereby atleast one step of the synthesis uses an enzymatic reaction to obtain anenantiomerically pure or enriched synthetic precursor of the desiredenantiomer;

v) Chemical asymmetric synthesis—a synthetic technique whereby thedesired enantiomer is synthesized from an achiral precursor underconditions that produce asymmetry (i.e., chirality) in the product,which may be achieved using chiral catalysts or chiral auxiliaries;

vi) Diastereomer separations—a technique whereby a racemic compound isreacted with an enantiomerically pure reagent (the chiral auxiliary)that converts the individual enantiomers to diastereomers. The resultingdiastereomers are then separated by chromatography or crystallization byvirtue of their now more distinct structural differences and the chiralauxiliary later removed to obtain the desired enantiomer;

vii) First- and second-order asymmetric transformations—a techniquewhereby diastereomers from the racemate equilibrate to yield apreponderance in solution of the diastereomer from the desiredenantiomer or where preferential crystallization of the diastereomerfrom the desired enantiomer perturbs the equilibrium such thateventually in principle all the material is converted to the crystallinediastereomer from the desired enantiomer. The desired enantiomer is thenreleased from the diastereomer;

viii) Kinetic resolutions—this technique refers to the achievement ofpartial or complete resolution of a racemate (or of a further resolutionof a partially resolved compound) by virtue of unequal reaction rates ofthe enantiomers with a chiral, non-racemic reagent or catalyst underkinetic conditions;

ix) Enantiospecific synthesis from non-racemic precursors—a synthetictechnique whereby the desired enantiomer is obtained from non-chiralstarting materials and where the stereochemical integrity is not or isonly minimally compromised over the course of the synthesis;

x) Chiral liquid chromatography—a technique whereby the enantiomers of aracemate are separated in a liquid mobile phase by virtue of theirdiffering interactions with a stationary phase (including via chiralHPLC). The stationary phase can be made of chiral material or the mobilephase can contain an additional chiral material to provoke the differinginteractions;

xi) Chiral gas chromatography—a technique whereby the racemate isvolatilized and enantiomers are separated by virtue of their differinginteractions in the gaseous mobile phase with a column containing afixed non-racemic chiral adsorbent phase;

xii) Extraction with chiral solvents—a technique whereby the enantiomersare separated by virtue of preferential dissolution of one enantiomerinto a particular chiral solvent;

xiii) Transport across chiral membranes—a technique whereby a racemateis placed in contact with a thin membrane barrier. The barrier typicallyseparates two miscible fluids, one containing the racemate, and adriving force such as concentration or pressure differential causespreferential transport across the membrane barrier. Separation occurs asa result of the non-racemic chiral nature of the membrane that allowsonly one enantiomer of the racemate to pass through.

xiv) Simulated moving bed chromatography, is used in one embodiment. Awide variety of chiral stationary phases are commercially available.

General Synthetic Route 1:

To a solution of commercially available3-chloro-6-methoxybenzo[b]thiophene-2-carbonyl chloride (Compound 1) isadded Weinreb's amine and base to afford Weinreb's amide 2. Weinreb'samide 2 is then subjected to the appropriate Grignard reagent to affordCompound 3. Compound 3 undergoes nucleophilic attack of intermediate 4to afford Compound 5. Compound 5 is then demethylated to afford Compound6.

To a solution of commercially available3-chloro-6-methoxybenzo[b]thiophene-2-carbonyl chloride (Compound 1) isadded Weinreb's amine and base to afford Weinreb's amide 2. Weinreb'samide 2 is then subjected to the appropriate Grignard reagent to affordCompound 3. Compound 3 undergoes nucleophilic attack of intermediate 7to afford Compound 5. Compound 8 is then demethylated to afford Compound9.

To a solution of commercially available3-chloro-6-methoxybenzo[b]thiophene-2-carbonyl chloride (Compound 1) isadded Weinreb's amine and base to afford Weinreb's amide 2. Weinreb'samide 2 is then subjected to the appropriate Grignard reagent to affordCompound 3. Compound 3 undergoes nucleophilic attack of intermediate 10to afford Compound 11. Compound 11 is then demethylated to affordCompound 12.

To a solution of commercially available3-chloro-6-methoxybenzo[b]thiophene-2-carbonyl chloride (Compound 1) isadded Weinreb's amine and base to afford Weinreb's amide 2. Weinreb'samide 2 is then subjected to the appropriate Grignard reagent to affordCompound 3. Compound 3 undergoes nucleophilic attack of intermediate 13to afford Compound 14. Compound 14 is then demethylated to affordCompound 15.

To a solution of commercially available3-chloro-6-methoxybenzo[b]thiophene-2-carbonyl chloride (Compound 1) isadded Weinreb's amine and base to afford Weinreb's amide 2. Weinreb'samide 2 is then subjected to the appropriate Grignard reagent to affordCompound 3. Compound 3 undergoes nucleophilic attack of intermediate 16to afford Compound 17. Compound 17 is then demethylated to affordCompound 18.

To a solution of commercially available3-chloro-6-methoxybenzo[b]thiophene-2-carbonyl chloride (Compound 1) isadded Weinreb's amine and base to afford Weinreb's amide 2. Weinreb'samide 2 is then subjected to the appropriate Grignard reagent to affordCompound 3. Compound 3 undergoes nucleophilic attack of intermediate 19to afford Compound 20. Compound 20 is then demethylated to affordCompound 21.

In Step 1 the primary alcohol of commercially available Compound 22 isconverted to Compound 23 by methods known in the art. In Step 2 Compound23 is subjected to nucleophilic attack by a R² group to affordIntermediate 4 which is used in Scheme 1.

Scheme 8 is a non-limiting example of the method described in Scheme 7.In Step 1 the primary alcohol of commercially available4-(2-Hydroxyethyl)phenol 24 is subjected to concentrated hydrochloricacid in a microwave to afford Compound 25. In Step 2 Compound 25 ismixed with azetidine in nucleophilic conditions to afford Compound 26which can be used in Scheme 1.

In Step 1 the chloro group of commercially available Compound 27 issubjected to nucleophilic attack by a R² group to afford Intermediate28. In Step 2 Compound 28 is converted to a Grignard Reagent as known inthe art to afford Intermediate 16 which is used in Scheme 4.

Scheme 10 is a non-limiting example of the method described in Scheme 8.In Step 1 the chloro group of commercially available1-bromo-4-(2-chloroethoxy)benzene 29 is subjected to diethyl amine undernucleophilic conditions to afford Compound 30. In Step 2 Compound 30 ismixed with magnesium to afford Compound 31 which can be used in Scheme4.

Example 1 Representative Compounds of the Present Invention

Table 1 and Table 2 provide non-limiting examples of compounds of thepresent invention which can be made according to the procedures above orin Example 2. Example 2 also provides detailed synthetic procedures forcompounds 100-112 and compounds 120 and 121. One of ordinary skill inthe art will be able to use these procedures or routine modificationsthereof to prepare compounds described herein.

TABLE 1 Compound # Structure Name 100

(3-(4-(2-(ethylamino)ethyl)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(4-fluoro- 2,6-dimethylphenyl)methanone 101

(4-fluoro-2,6-dimethylphenyl)(6- hydroxy-3-(4-(piperidin-1-yl)phenoxy)benzo[b]thiophen-2- yl)methanone 102

(3-(4-(azepan-1-yl)phenoxy)-6- hydroxybenzo[b]thiophen-2-yl)(4-fluoro-2,6-dimethylphenyl)methanone 103

(4-fluoro-2,6-dimethylphenyl)(6- hydroxy-3-(4-(piperidin-3-yl)phenoxy)benzo[b]thiophen-2- yl)methanone 104

(3-(4-(2-aminoethyl)phenoxy)-6- hydroxybenzo[b]thiophen-2-yl)(4-fluoro-2,6-dimethylphenyl)methanone 105

(4-fluoro-2,6-dimethylphenyl)(6- hydroxy-3-(4-(2-(isopropylamino)ethyl)phenoxy)benzo[b]thiophen- 2-yl)methanone 106

(4-fluoro-2,6-dimethylphenyl)(6- hydroxy-3-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)benzo[b]thiophen-2- yl)methanone 107

(3-(4-(2-(azepan-1-yl)ethoxy)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(4- fluoro-2,6-dimethylphenyl)methanone108

(4-fluoro-2,6-dimethylphenyl)(6- hydroxy-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenoxy)benzo[b]thiophen-2- yl)methanone 109

(4-fluoro-2,6-dimethylphenyl)(6- hydroxy-3-(4-(2-(pentan-3-ylamino)ethyl)phenoxy)benzo[b]thiophen- 2-yl)methanone 110

(3-(4-(2- (cyclohexylamino)ethyl)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(4-fluoro- 2,6-dimethylphenyl)methanone 111

(3-(4-(2-(sec- butylamino)ethyl)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(4-fluoro- 2,6-dimethylphenyl)methanone 112

(3-(4-(2-(diethylamino)ethyl)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(4-fluoro- 2,6-dimethylphenyl)methanone 113

(4-fluoro-2,6-dimethylphenyl)(6- hydroxy-3-(4-((methylamino)methyl)phenoxy)benzo[b]thiophen- 2-yl)methanone 114

(3-(4-((dimethylamino)methyl)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(4- fluoro-2,6-dimethylphenyl)methanone115

(3-(4-(aminomethyl)phenoxy)-6- hydroxybenzo[b]thiophen-2-yl)(4-fluoro-2,6-dimethylphenyl)methanone 116

(4-fluoro-2,6-dimethylphenyl)(6- hydroxy-3-(4-(3-(methylamino)propyl)phenoxy)benzo[b]thiophen- 2-yl)methanone 117

(4-fluoro-2,6-dimethylphenyl)(3-(4-(2- (3-(fluoromethyl)azetidin-1-yl)ethyl)phenoxy)-6- hydroxybenzo[b]thiophen-2- yl)methanone 118

(S)-(4-fluoro-2,6-dimethylphenyl)(6-hydroxy-3-(4-(2-(3-methylpyrrolidin-1-yl)ethyl)phenoxy)benzo[b]thiophen-2- yl)methanone 119

(4-fluoro-2,6-dimethylphenyl)(3-(4-(2- (3-(fluoromethyl)azetidin-1-yl)ethyl)phenyl)-6- hydroxybenzo[b]thiophen-2- yl)methanone 120

(4-f1uoro-2,6-dimethylphenyl)(3-(4-(2- (3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6- hydroxybenzo[b]thiophen-2- yl)methanone 121

1-(2-(4-(2-(4-fluoro-2,6- dimethylbenzoyl)-6- hydroxybenzo[b]thiophen-3-yl)phenoxy)ethyl)azetidin-3-one 122

1-(2-(4-(2-(4-fluoro-2,6- dimethylbenzoyl)-6- hydroxybenzo[b]thiophen-3-yl)phenoxy)ethyl)azetidine-3-carboxylic acid 123

(4-fluoro-2,6-dimethylphenyl)(3-(4-(2- (3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-6- hydroxybenzo[b]thiophen-2- yl)methanone 124

(4-fluoro-2,6-dimethylphenyl)(3-(4-(2- (4-(fluoromethyl)piperidin-1-yl)ethoxy)phenyl)-6- hydroxybenzo[b]thiophen-2- yl)methanone 125

(6-(benzyloxy)-3-(4-(2- hydroxyethoxy)phenyl)benzo[b]thiophen-2-yl)(4-fluoro-2,6- dimethylphenyl)methanone

TABLE 2 Compound # Structure Name 126

sodium 1-(2-(4-(2-(4-fluoro-2,6- dimethylbenzoyl)-6-oxidobenzo[b]thiophen-3- yl)phenoxy)ethyl)azetidine-3-carboxylate 127

(4-fluoro-2,6-dimethylphenyl)(6-hydroxy- 3-(4-(2-(3-methylpyrrolidin-1-yl)ethyl)phenoxy)benzo[b]thiophen-2- yl)methanone 128

(R)-(4-fluoro-2,6-dimethylphenyl)(6-hydroxy-3-(4-(2-(3-methylpyrrolidin-1-yl)ethyl)phenoxy)benzo[b]thiophen-2- yl)methanone 129

(R)-(4-fluoro-2,6-dimethylphenyl)(6- hydroxy-3-(4-(piperidin-3-yl)phenoxy)benzo[b]thiophen-2- yl)methanone 130

(S)-(4-fluoro-2,6-dimethylphenyl)(6- hydroxy-3-(4-(piperidin-3-yl)phenoxy)benzo[b]thiophen-2- yl)methanone 131

(S)-(4-fluoro-2,6-dimethylphenyl)(3-(4-(2-(3-(fluoromethyl)pyrrolidin-1- yl)ethoxy)phenyl)-6-hydroxybenzo[b]thiophen-2-yl)methanone 132

(R)-(4-fluoro-2,6-dimethylphenyl)(3-(4-(2-(3-(fluoromethyl)pyrrolidin-1- yl)ethoxy)phenyl)-6-hydroxybenzo[b]thiophen-2-yl)methanone 133

(4-fluoro-2,6-dimethylphenyl)(6-hydroxy- 3-(4-(2-hydroxyethoxy)phenyl)benzo[b]thiophen- 2-yl)methanone

Example 2. Representative Synthetic Procedures Synthesis of Compound 100((3-(4-(2-(Ethylamino)ethyl)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(4-fluoro-2,6-dimethylphenyl)methanone)

In Step 1, 100 grams of Compound 32 was dissolved thionyl chloride andpyridine. Methanol was added to the solution to afford Compound 33.Compound 33 was recrystallized to obtain 50 grams of pure product. TheH-NMR was clean. In Step 2, 25 grams of Compound 32 was subjected to 1.3eq of n-butyl lithium and Compound 34. After column purification 9.8grams of pure Compound 35 was isolated. The H-NMR was clean. In Step 3,3.5 grams of Compound 35 was reacted with Boc-anhydride in the presenceof triethylamine to afford 5 grams of Compound 37 after work-up andpurification. In Step 4, 4.5 grams of Compound 37 was dissolved in DMFand then Cesium Carbonate and Compound 35 were added to afford Compound38. Compound 38 was purified by column chromatography to afford 6.8grams of pure compound. H-NMR was clean and HPLC purity was 96%. In Step5, to a solution of 6.2 grams of Compound 38 in DMF was added iodoethaneand sodium hydride. After work-up and column purification 4.4 grams ofCompound 39 was isolated. H-NMR was clean. In Step 6, 2 grams ofCompound 39 was exposed to BBr₃ to afford Compound 100. H-NMR was clean.HPLC purity was 96.5%.

Synthesis of Compound 101(((4-Fluoro-2,6-dimethylphenyl)(6-hydroxy-3-(4-(piperidin-1-yl)phenoxy)benzo[b]thiophen-2-yl)methanone)

In Step 1, 1.67 grams of Compound 40 was converted to Compound 41 by theCham Iam coupling with copper acetate. The H-NMR was clean. In Step 2,0.51 grams of Compound 41 was subjected to BBr₃ to afford 130 milligramsof Compound 42. The H-NMR was clean. In Step 3, 85 milligrams ofCompound 42 was dissolved in DMF and then Cesium Carbonate and Compound35 were added to afford 81 milligrams of Compound 43. H-NMR was clean.In Step 4, 50 milligrams of Compound 43 was exposed to BBr₃ to afford 10milligrams of Compound 101 after purification. H-NMR was clean. HPLCpurity was 95.3%.

Synthesis of Compound 102((3-(4-(Azepan-1-yl)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(4-fluoro-2,6-dimethylphenyl)methanone)

In Step 1, 1 gram of Compound 40 and 3 equivalents of azepane wereconverted to 353 milligrams of Compound 44 by the Cham lam coupling withcopper acetate. In Step 2, 353 milligrams of Compound 44 was subjectedto BBr₃ to afford 235 milligrams of Compound 45 after columnchromatography. In Step 4, 210 milligrams of Compound 46 was exposed toBBr₃ in DCM to afford 30 milligrams of Compound 102 after work-up andcolumn chromatography. H-NMR was clean. HPLC purity was 98.8%.

Synthesis of Compound 103((4-fluoro-2,6-dimethylphenyl)(6-hydroxy-3-(4-(piperidin-3-yl)phenoxy)benzo[b]thiophen-2-yl)methanone)

In Step 1, 1.6 grams of Compound 40 was converted to 1.6 grams ofCompound 47 by the Suzuki coupling. The H-NMR was clean. In Step 2, 800milligrams of Compound 47 was reduced by Platinum Oxide in the presenceof hydrogen gas, isopropyl amine, and 6N HCl to afford 600 milligrams ofCompound 48. The H-NMR was clean. In Step 3, 186 milligrams of Compound48 was dissolved in DCM and then subjected to BBr₃ to afford Compound49. The crude mixture of Compound 49 was then quenched with water andadjusted to pH 9 with potassium carbonate. The resulting mixture wasexposed in Step 4 to Boc-anhydride to afford 100 milligrams of Compound50 after work-up and purification. The H-NMR was clean. In Step 5, 100milligrams of Compound 50 was dissolved in DMF and then Cesium Carbonateand Compound 35 were added to at 70° C. to afford 169 milligrams ofCompound 51 after work-up and purification. In Step 6, 40 milligrams ofCompound 51 was exposed to BBr₃ to afford 20 milligrams of Compound 103after purification. H-NMR was clean. HPLC purity was 97%.

Synthesis of Compound 104(((3-(4-(2-Aminoethyl)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(4-fluoro-2,6-dimethylphenyl)methanone)and Compound 105((4-Fluoro-2,6-dimethylphenyl)(6-hydroxy-3-(4-(2-(isopropylamino)ethyl)phenoxy)benzo[b]thiophen-2-yl)methanone)

In Step 1, 100 milligrams of Compound 38 was dissolved in DCM and thensubjected to BBr₃ to afford 86 milligrams of Compound 104. HPLC puritywas 96.5%. The H-NMR was clean. In Step 2, 86 milligrams of Compound 104was subjected to reductive amination conductions with sodiumcyanoborohydride, acetone, and acetic acid to afford crude Compound 105.The crude mixture was worked-up and purified by column chromatographyand then concentrated under high vacuum for 24 hours and then dissolvedin methanol and concentrated to dryness to afford 15 milligrams ofCompound 105. The H-NMR was clean. HPLC purity was >990/%.

Synthesis of Compound 106(((3-(4-(2-Aminoethyl)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(4-fluoro-2,6-dimethylphenyl)methanone)

In Step 1, 1 gram of Compound 35 was dissolved in DCM and then subjectedto BBr₃ to afford 930 milligrams of Compound 52. The H-NMR was clean. InStep 2, Compound 52 was reacted with sodium hydride and benzyl bromideto afford Compound 53. In Step 3, 200 milligrams of Compound 33 wasdissolved in DCM and triethylamine and reacted with 2-chloroacetylchloride to afford 240 milligrams of Compound 54 after work-up andpurification. In Step 4 Compound 54 was then dissolved in DMF andreacted with sodium hydride and 4-(benzyloxy)phenol to afford 300milligrams of Compound 55 after work-up and purification. In Step 5, 300milligrams of Compound 55 was reduced by lithium aluminum hydride toafford 260 milligrams of Compound 56 as an oil after work-up andpurification. The H-NMR was clean. In Step 6, 260 milligrams of Compound56 was hydrogenated to afford 200 milligrams of Compound 57. The H-NMRwas clean. In Step 8, 100 milligrams of Compound 57 was mixed withCompound 53 in DMF in the presence of cesium carbonate to afford 160milligrams of Compound 58. In Step 10, 30 milligrams of Compound 58 washydrogenated with palladium on carbon in the presence of hydrogen gas toafford 20 milligrams of Compound 106 after work-up and purification.

Synthesis of Compound 107((3-(4-(2-(Azepan-1-yl)ethoxy)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(4-fluoro-2,6-dimethylphenyl)methanone)

In Step 1, 500 milligrams of Compound 59 was reacted with 2-chloroacetylchloride to afford 930 milligrams of crude Compound 60. In Step 2, 500milligrams of crude Compound 60 was converted to 489 milligrams ofCompound 61 after work-up and purification. The H-NMR was clean. In Step3, 489 milligrams of Compound 61 was reduced by lithium aluminum hydrideto afford 376 milligrams of Compound 62 after work-up and purification.The H-NMR was clean. In Step 4, 376 milligrams of Compound 62 washydrogenated to afford 174 milligrams of Compound 63 after work-up andcolumn purification. The H-NMR was clean. In Step 5, 174 milligrams ofCompound 63 was mixed with Compound 53 in DMF in the presence of cesiumcarbonate to afford 190 milligrams of Compound 64 after work-up andpurification. The H-NMR was clean. In Step 6, 90 milligrams of Compound64 was hydrogenated with palladium on carbon in the presence of hydrogengas to afford 20 milligrams of Compound 107 after work-up andpurification. The H-NMR was clean except some residual solvent.

Synthesis of Compound 108((4-Fluoro-2,6-dimethylphenyl)(6-hydroxy-3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenoxy)benzo[b]thiophen-2-yl)methanone)

In Step 1, 500 milligrams of Compound 65 was reacted with 2-chloroacetylchloride to afford 677 milligrams of Compound 66 after work-up andpurification. In Step 2, 677 milligrams Compound 66 was converted to 987milligrams of Compound 67 after work-up and purification. The H-NMR wasclean. In Step 3, 987 milligrams of Compound 67 was reduced by lithiumaluminum hydride to afford 600 milligrams of Compound 68 after work-upand purification. The H-NMR was clean. In Step 4, 600 milligrams ofCompound 68 was hydrogenated to afford 359 milligrams of Compound 69after work-up and column purification. The H-NMR was clean. In Step 5,88 milligrams of Compound 69 was mixed with Compound 53 in DMF in thepresence of cesium carbonate to afford 160 milligrams of Compound 70after work-up and purification. The H-NMR was clean except for someresidual DMF. In Step 6, 50 milligrams of Compound 70 was hydrogenatedwith palladium on carbon in the presence of hydrogen gas to afford 13milligrams of Compound 108 after work-up and purification. The H-NMR wasclean.

Synthesis of Compound 109(4-Fluoro-2,6-dimethylphenyl)(6-hydroxy-3-(4-(2-(pentan-3-ylamino)ethyl)phenoxy)benzo[b]thiophen-2-yl)methanone

In Step 1, 50 milligrams of Compound 104 was subjected to reductiveamination in the presence of pentan-3-one to afford Compound 109.

Synthesis of Compound 110(3-(4-(2-(Cyclohexylamino)ethyl)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(4-fluoro-2,6-dimethylphenyl)methanone

In Step 1, 50 milligrams of Compound 104 was subjected to reductiveamination in the presence of cyclohexanone to afford 20 milligrams ofCompound 110 after work-up and purification. The H-NMR was clean. TheHPLC purity was 96.7%.

Synthesis of Compound 111(3-(4-(2-(Sec-butylamino)ethyl)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(4-fluoro-2,6-dimethylphenyl)methanone

In Step 1, 50 mg of Compound 104 was subjected to reductive amination inthe presence of pentan-2-one to afford 30 milligrams of Compound 111after work-up and purification. The H-NMR was clean. The HPLC purity was96%.

Synthesis of Compound 112(3-(4-(2-(Diethylamino)ethyl)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(4-fluoro-2,6-dimethylphenyl)methanone

In Step 1, 50 mg of Compound 104 was subjected to reductive amination inthe presence of acetaldehyde to afford 12 milligrams of Compound 112after work-up and purification. The H-NMR was clean. The HPLC purity was97.8%.

Synthesis of Compound 120(4-Fluoro-2,6-dimethylphenyl)(3-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6-hydroxybenzo[b]thiophen-2-yl)methanone

In Step 1, 500 mg 71 was alkylated with 2-bromoethanol in the presenceof K₂CO₃ in DMF at 80° C. to provide 500 mg of 72 after purification. InStep 2, 100 mg of 72 was borylated to afford 100 mg of 73 afterpurification. In Step 3, 240 mg of 52 was alkylated with benzyl bromidein the presence of sodium hydride in DMF to provide 250 mg of 53 afterpurification. In Step 4, 550 mg of 73 and 1.1 g of 53 was reacted in thepresence of Pd(PPh₃)₄ and K₂CO₃ in toluene and water at 100° C. toprovide 150 mg of Compound 12 after purification. In Step 5, 20 mg ofCompound 125 was reacted with tosyl chloride and triethylamine indichloromethane to provide 19 mg of 75 after purification. In Step 6, 17mg of 75 was reacted with crude 3-(fluoromethyl)azetidine (prepared bydeprotection of tert-butyl 3-(fluoromethyl)azetidine-1-carboxylate withtrifluoroacetic acid in dichloromethane) in the presence of K₂CO₃ inacetonitrile to provide Compound 120.

Synthesis of Compound 1211-(2-(4-(2-(4-Fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)phenoxy)ethyl)azetidin-3-one

In Step 1, 500 mg of 75 was reacted with sodium azide in acetonitrile at60° C. to provide 400 mg of 77 after purification. In Step 2, 270 mg of77 was reacted with triphenylphosphine and water at 60° C. to provide200 mg of 78 after purification. In Step 3, 78 was reacted withepichlorohydrin at room temperature over three days to provide a crudemixture in a 2.5 to 1 ratio of 79:78. In Step 4, the crude mixture inthe previous step was heated to 60° C. for two days to provide 150 mg of80 upon purification.

Example 3. Human ERα Reporter Assay

All reagents used in this assay was supplied in the Human ERα ReporterAssay by Indigo Biosciences # IB00401. In an effort to screen selectiveestrogen receptor degraders (SERDs), the Human ERα Reporter Assay,supplied by Indigo Biosciences, was utilized to quantify antagonistfunctional activity against the human estrogen receptor. Reporter cellswere thawed at 37° C. and added to pre-warmed to 37° C. cell recoverymedium (CRM). Stock concentration of 17β-estradiol was serially dilutedin CRM. Diluted 17β-estradiol was added to CRM containing reporter cellsresulting in a working concentration of 1.6 nM (2×). Cells plus17β-estradiol were dispensed in a kit-supplied white walled 96-wellplate. Concentrated stocks of test compounds were diluted to 2× workingconcentrations in cell screening medium (CSM). 2× concentrated compoundswere added to the plated cells in a dose-dependent manner resulting in afinal concentration range of 1E-11 to 1E-5 M and a final 17β-estradiolconcentration of 8E-10 M. Assay plates were incubated for 24 hours in ahumidified 37° C. incubator. Culture medium was removed from the assayplates by inversion. Detection substrate and buffer was warmed to roomtemperature, mixed thoroughly, and immediately added to the assayplates. Assay plates were incubated for 15 minutes at room temperatureprotected from light. Luminescence was measured in a Synergy HTXluminescence plate reader. Data is processed utilizing GraphPad Prism 7by graphing the relative light units measured at each compoundconcentration. This procedure was used to produce the graph in FIG. 1,FIG. 9, FIG. 10, FIG. 11, FIG. 12, FIG. 13, and FIG. 14.

Example 4. Estrogen Receptor (ER) Degradation Assay

A screening strategy was implemented utilizing an In-Cell Western assayto measure their ability to degrade the estrogen receptor in vitro. MCF7cells, which are estrogen receptor positive, were plated at a celldensity of 3.5E-05 cells/mL into black walled clear bottom 96-wellplates. Cells were incubated in phenol red free Dulbecco's ModifiedEagle Media (DMEM) supplemented with 8% charcoal-stripped fetal bovinecalf serum for 24 hours in a humidified 37° C. incubator. Concentratedstock compounds were diluted to 10× in complete media. Compounds wereadded to the plated cells in a dose-dependent manner ranging from 1E-12to 1E-05 M and incubated for an additional 24 hours at 37° C. Culturemedium was removed from the culture plates by gentle inversion. Cellswere fixed in 4% paraformaldehyde in 1× phosphate bufferedsaline-calcium magnesium free (PBS-CMF) for 15 minutes at roomtemperature, washed 3 times for 5 minutes each in 1×PBS-CMF. Cells werepermeabilized in immunofluorescence (IF) blocking buffer (Cell Signaling#12411) containing 0.3% Triton X100. Cells were washed 3 times for 5minutes each in 1×PBS-CMF and incubated in estrogen receptor α (D6R2W)rabbit primary antibody (Cell Signaling #13258) diluted 1:300 in IFantibody dilution buffer (Cell Signaling #12378). Cells were washed 3times for 5 minutes each in 1×PBS-CMF and stained with goat anti-rabbit(Biotium #CF770) secondary antibody diluted 1:2000 in IF antibodydilution buffer and normalizing stain CellTag 700 diluted 1:500 (Licor#926-41090). ER protein expression was assessed by the Licor Odyssey CLximaging system using Image Studio v5.2. Data is processed utilizingGraphPad Prism 7 by subtracting background from the vehicle and settingthe vehicle to 100% ER activity, followed by comparing treated samplesto vehicle. This procedure was used to produce the graph in FIG. 2, FIG.3, FIG. 4, FIG. 5, FIG. 6, FIG. 7, and FIG. 8.

Example 5. Data from Human ERα Reporter Assay and Estrogen Receptor (ER)Degradation Assay

The procedures in Example 3 and Example 4 were used to produce the dataprovided in Table 3 below. In the below table for the Estrogen ReceptorDegradation Assay and the Human ERα Reporter Assay:

*** denotes a <1 μM; IC₅₀;

** denotes a <50 μM IC₅₀; and

* denotes a >51 μM IC₅₀.

In the below table for the % Estrogen Receptor Remaining:

**** denotes 0-40% Estrogen Receptor remaining

*** denotes 41-70% Estrogen Receptor remaining

** denotes 71-90% Estrogen Receptor remaining

* denotes 91-100% Estrogen Receptor remaining

TABLE 3 Estrogen Receptor Human ERα % Estrogen Comp. DegradationReporter Receptor # Structure Assay IC₅₀ Assay IC₅₀ Remaining 100

*** *** **** 101

*** *** *** 102

*** *** *** 103

** *** **** 104

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The materials and methods of the appended claims are not limited inscope by the specific materials and methods described herein, which areintended as illustrations of a few aspects of the claims and anymaterials and methods that are functionally equivalent are within thescope of this disclosure. Various modifications of the materials andmethods in addition to those shown and described herein are intended tofall within the scope of the appended claims. Further, while onlycertain representative materials, methods, and aspects of thesematerials and methods are specifically described, other materials andmethods and combinations of various features of the materials andmethods are intended to fall within the scope of the appended claims,even if not specifically recited. Thus a combination of steps, elements,components, or constituents can be explicitly mentioned herein; however,all other combinations of steps, elements, components, and constituentsare included, even though not explicitly stated.

I claim:
 1. A compound selected from:

or a pharmaceutically acceptable salt thereof; wherein A is:

m is 0, 1, or 2; n is 1, 2, or 3; o is 0, 1, 2, 3, 4, or 5; Z isselected from —O—, —C(R³)₂—, —CHR³—, —CH₂—, —CHF—, —CF₂—, and —S—; Z_(A)and Z_(B) are independently selected from —O—, —C(R³)₂—, —CHR³—, —CH₂—,—CHF—, —CF₂—, and —S—; each R¹ is independently selected fromC₁-C₃alkyl, halogen, and C₁-C₃haloalkyl; R² is selected from: a. 4-6membered heterocycle optionally substituted with one, two, or threegroups independently selected from R⁴; b. —NH₂, —NH(C₁-C₃alkyl orC₂-C₃haloalkyl), and —N((independently)C₁-C₃alkyl or C₂-C₃haloalkyl)₂;c. monocyclic 7-8 membered heterocycle optionally substituted with one,two, or three groups independently selected from R⁴; and d. 6-12membered bicyclic or bridged heterocycle optionally substituted withone, two, or three groups independently selected from R⁴; R³ isindependently selected from —F, —Cl, —Br, —CH₃, —CH₂F, —CHF₂, and —CF₃;R⁴ is selected from hydrogen, halogen, C₁-C₃alkyl, and C₁-C₃haloalkyl;and R⁵ is selected from hydrogen, halogen, C₁-C₃alkyl, andC₁-C₃haloalkyl.
 2. The compound of claim 1, of Formula:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1, of Formula:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, wherein Z is —O—.
 5. The compound of claim 1, wherein o is
 3. 6. Thecompound of claim 1 selected from Formula:

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, wherein at least one R¹ is fluoro.
 8. The compound of claim 1,wherein at least one R¹ is methyl.
 9. The compound of claim 1, whereinR² is —N(CH₂CH₃)₂.
 10. The compound of claim 1, wherein R² is selectedfrom


11. A compound selected from:

or a pharmaceutically acceptable salt thereof, wherein A is:

Y is

m is 0, 1, or 2; n is 1, 2, or 3; o is independently 0, 1, 2, 3, 4, or5; Z is selected from —O—, —C(R³)₂—, —CHR³—, —CH₂—, —CHF—, —CF₂—, and—S—; Z_(A) and Z_(B) are independently selected from —O—, —C(R³)₂—,—CHR³—, —CH₂—, —CHF—, —CF₂—, and —S—; each R¹ is independently selectedfrom C₁-C₃alkyl, halogen, and C₁-C₃haloalkyl; R² is selected from: a.4-6 membered heterocycle optionally substituted with one, two, or threegroups independently selected from R⁴; b. —NH₂, —NH(C₁-C₃alkyl orC₂-C₃haloalkyl), and —N((independently)C₁-C₃alkyl or C₂-C₃haloalkyl)₂;c. monocyclic 7-8 membered heterocycle optionally substituted with one,two, or three groups independently selected from R⁴; d. 6-12 memberedbicyclic or bridged heterocycle optionally substituted with one, two, orthree groups independently selected from R⁴; and e. hydroxyl, alkoxy,—NH—(CH₂)_(n1)—NH₂, —NH—(CH₂)_(n1)—NH(C₁-C₁₂alkyl or C₂-C₁₂haloalkyl),—NH—(CH₂)_(n1)—N((independently)C₁-C₁₂alkyl or C₂-C₁₂haloalkyl),—NHC₄-C₁₂alkyl, and —N(C₁-C₁₂alkyl)₂; n1 is 2, 3, 4, 5, or 6; R³ isindependently selected from —F, —Cl, —Br, —CH₃, —CH₂F, —CHF₂, and —CF₃;R⁴ is selected from hydrogen, halogen, C₁-C₃alkyl, and C₁-C₃haloalkyl;or R⁴ is selected from hydrogen, halogen, C₁-C₃alkyl, C₁-C₃haloalkyl,—COOH, —COOC₁-C₁₂alkyl, —CONH₂, —CON(H)alkyl, and —CON(alkyl)₂; R⁵ isselected from hydrogen, halogen, C₁-C₃alkyl, and C₁-C₃haloalkyl; and R⁷is a 4, 5, 6, 7, 8, 9, or 10 membered heterocycle optionally substitutedwith 1, 2, or 3 groups selected from R⁴.
 12. The compound of claim 11selected from

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim11 selected from

or a pharmaceutically acceptable salt thereof.
 14. The compound of claim11 selected from:

or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1 or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.